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Will the resection of pheochromocytoma improve preoperative diabetes mellitus?
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Asian Journal of Surgery xxx (xxxx) xxx
Available online at www.sciencedirect.com
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ORIGINAL ARTICLE
Will the resection of pheochromocytoma improve preoperative diabetes mellitus? Zheng-Huan Liu a,1, Liang Zhou a,1, Le-De Lin a, Tao Chen b, Qing-Yao Jiang a, Zhi-Hong Liu a, Kun-Jie Wang a, Yu-Chun Zhu a,*, Hong Li a,**, Yan Ren b a Department of Urology, Institute of Urology (Laboratory of Reconstructive Urology), West China Hospital, Sichuan University, Chengdu, Sichuan, PR China b Department of Endocrinology and Metabolism, Adrenal Center, West China Hospital, Sichuan University, Guo Xue Xiang 37, Chengdu, 610000, Sichuan, PR China
Received 12 November 2018; received in revised form 8 January 2019; accepted 22 January 2019
KEYWORDS Diabetes mellitus; Development; Pheochromocytoma; Risk factor
Summary Objective: To explore the likelihood of resolution of diabetes postoperatively. Besides, we would like to determine the risk factors associated with development and prognosis of diabetes. Methods: All patients in our hospital undergoing surgical removal of pheochromocytoma (PHEO) from 10 October 2010 to 21 July 2017 were retrospectively analyzed to determine those with preoperative diabetes. Preoperatively demographic data and information on diabetes were recorded. The median follow-up was 45.2 months. Results: Finally, 67 (36.2%) patients were with diabetes among 185 patients undergoing surgery. Furthermore, 47 patients had complete follow-up. And 37 (78.7%) patients had improvement of diabetes after resection of PHEO. In details, 29 (61.7%) patients had complete resolution. Older patients were more likely to develop diabetes, and symptomatic patients with longer course of PHEO were also more susceptible to preoperative diabetes. Elevated body mass index (BMI) was a risk factor of persistent diabetes postoperatively after surgery. Conclusions: 36.2% of PHEO patients might be with preoperative diabetes mellitus. Older patients were more likely to present diabetes preoperatively. And the increasing length of PHEO course might be another risk factor on developing diabetes preoperatively. Resection of tumors improved diabetes in 78.7% of patients, with resolution in 61.7%. Patients with higher BMI might need treatment for diabetes postoperatively.
* Corresponding authors: West China Hospital, Sichuan University, Guo Xue Xiang 37, Chengdu, 610000, Sichuan, PR China. Fax: þ86 28 8542 2451. ** Corresponding authors: West China Hospital, Sichuan University, Guo Xue Xiang 37, Chengdu, 610000, Sichuan, PR China. Fax: þ86 28 8542 2451. E-mail addresses: [email protected] (Y.-C. Zhu), [email protected] (H. Li). 1 Zheng-Huan Liu and Liang Zhou have contributed equally to this work. https://doi.org/10.1016/j.asjsur.2019.01.012 1015-9584/ª 2019 Asian Surgical Association and Taiwan Robotic Surgery Association. Publishing services by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Please cite this article as: Liu Z-H et al., Will the resection of pheochromocytoma improve preoperative diabetes mellitus?, Asian Journal of Surgery, https://doi.org/10.1016/j.asjsur.2019.01.012
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Z.-H. Liu et al. ª 2019 Asian Surgical Association and Taiwan Robotic Surgery Association. Publishing services by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http:// creativecommons.org/licenses/by-nc-nd/4.0/).
1. Introduction Pheochromocytoma is a rare tumor producing catecholamine that is aroused from chromaffin cells of the adrenal medulla.1 The most well-known symptoms and signs of PHEO are hypertension, headaches, palpitations, sweating and weight loss. Besides, a range of authors have concluded that glucose intolerance and type 2 DM may be the firstly presented symptoms in approximately 50% of PHEO patients. However, there are almost no large studies, especially in China, which have talked about the long-term prognosis of such patients after surgery. In addition, 15e35% of patients with PHEO could be complicated with impaired glucose tolerance or diabetes.2,3 Not only The decreased glucose uptake, but also the increased gluconeogenesis and glycogenolysis are associated with elevated catecholamine.3 Besides, increased catecholamine may result in increased insulin resistance as well as decreased insulin secretion.4 However, the previous researches have shown quick recovery of insulin resistance and insulin secretion after resection of PHEO. Furthermore, we can even see postoperative hypoglycemia in patients without preoperative diabetes.2,4 Additionally, a recent research has shown that diabetes might occur more often in patients with large, symptomatic PHEO. Most of them could have the long-term postoperative resolution of diabetes, but patients with the higher BMI might still need treatment of diabetes after successful removal of tumors.5 However, there are little data available regarding such outcomes of patients with PHEO in China. Therefore, we performed this study to explore the prevalence of diabetes in PHEO patients and the prognosis after removal of tumors. Furthermore, we would like to identify the possible risk factors related to the prognosis of diabetes.
2. Methods All patients in West China Hospital who underwent surgical removal of PHEO from 10 October 2010 to 21 July 2017 were included in the study. And demographic data like sex, age, Body Mass Index (BMI) were all collected through the retrospective chart review. Furthermore, tumor size and the absence or presence of symptoms preoperatively were also collected. In addition, we had examined patients’ either plasma or 24-h urine normetanephrine and metanephrine concentrations measurement to confirm the biochemical diagnosis of PHEO. However, the blood and urine tests were not always performed in the same patient. Therefore, we calculated the greatest fold increase for comparison. Hereafter, the fold change will be referred to as “catecholamines”. And we define patients with chief complains including hypertension, headaches, palpitations,
sweating and weight loss as symptomatic patients. As for the PHEO course, it refers to the duration from the first time when patients complain about their symptoms. Data on blood glucose and medication use for diabetes was also collected. Patients who were complicated with diabetes were defined as those already with documentation of a confirmed diagnosis of diabetes mellitus, use of diabetes medications, abnormal hemoglobin AlC level (6.5%), evidence of multiple abnormal fasting plasma glucose level (7.0 mmol/L) or random plasma glucose level (11.1 mmol/L).6 Besides, we determined the resolution of diabetes via patients’ and clinical reports and the documentation of medication adjustments. However, patients requiring steroids after surgical removal or with inadequate follow-up were all excluded from the analysis of this study.
2.1. Statistical analysis Statistical analysis was performed via SPSS version 22.0 (IBM Corporation, Armonk, NY, USA). Chi-square tests were performed to compare the categorical variables, and the Student’s t tests or Mann-Whitney U tests were used to analyze continuous parametric and nonparametric variables, respectively. And the p-value <0.05 was defined significantly difference. Multivariate analysis was performed via binary logistic regression.
3. Results In the study, there were 185 patients who accepted resection of the PHEO. All patients’ preoperative characteristics are shown in Table 1. Among all the 185 patients, 67 (36.2%) met the criteria because of the preoperative evidence of diabetes. And all the 67 patients complicated with type II diabetes were treated with preoperative medication (either oral medication or insulin). As shown in Table 2, we found that there was no statistical difference of sex or BMI between patients with diabetes and that without diabetes. Besides, there was also no statistical difference in the size and location of the tumors, so as the proportion of tumors presented as incidentaloma rather than as symptomatic (72.9 vs. 74.6). As for the median fold change in catecholamine levels between patients with and without diabetes, there was also no significant difference (p Z 0.343). However, patients who had diabetes were significantly older than those who did not (p < 0.001). Furthermore, we found that symptomatic patients with a longer course of PHEO were more likely to develop preoperative diabetes (p Z 0.006). At last, among 67 patients with preoperative diabetes, 47 had adequate follow-up to determine the prognosis of diabetes. These patients included 22 (32.8%) men and 45
Please cite this article as: Liu Z-H et al., Will the resection of pheochromocytoma improve preoperative diabetes mellitus?, Asian Journal of Surgery, https://doi.org/10.1016/j.asjsur.2019.01.012
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Resolution of diabetes mellitus after resection of PHEO Table 1 Preoperative characteristics of patients undergoing adrenalectomy for pheochromocytoma. Patient with pheochromocytoma (n Z 185) Male [n (%)] Female [n (%)] Age at surgery, years Body mass index Incidentaloma [n (%)] Symptomatic [n (%)] Tumor location [n (%)] Left Right Bilateral Extra-adrenal (paraganglioma) Size on preoperative imaging, cm Catecholamines (range) Fold change catecholamines (range) Diabetes [n (%)] No diabetes [n (%)]
71 (38.4) 114 (61.6) 47.2 13.7 21.7 3.6 49 (26.5) 136 (73.5)
Finally, we compared the differences between patients with resolution of diabetes and those without (Table 3). The BMIs of patients with complete or partial resolution of diabetes were significantly lower than those of patients without resolution (p Z 0.022). Patients with higher preoperative catecholamine fold changes and larger tumors were also more likely to resolve their diabetes, however, the relationships were both not significant.
4. Discussion
56 (30.3) 95 (51.4) 7 (3.8) 27 (14.6) 5.3 2.2 5154.3 (187.0e192374.0) 14.4 (0.5e538.9)
67 (36.2) 118 (63.8)
(67.2%) women. The mean age of them was (53.5 9.1) years. After a median follow-up of 45.2 months (range 12.7e83.1), There were 37 (78.7%) patients with either improvement or resolution of diabetes after resection of PHEO. In details, 29 (61.7%) patients got complete resolution, which was defined as being off medication with either evidence of fasting blood glucose or patients’ reports. And 8 (17.0%) patients were reported better glucose control with the reduced dose of medication. However, ten patients did not get any improvement after surgery. They all needed the same dose of medication for their diabetes and found no improvement in glucose control during the postoperative period.
Table 2
3
In the study, we had examined all patients in West China Hospital who underwent surgical removal of PHEO from 10 October 2010 to 21 July 2017 to determine both the prevalence of preoperative diabetes and the likelihood of being with normoglycemia after removal of PHEO. Besides, we also tried to identify the patients’ demographic or tumor characteristics that might have influence on the improvement of glucose intolerance or diabetes after removal of PHEO. There were 36.2% (67/185) of the PHEO patients being with diabetes mellitus. It is higher than the incidence rate ranged from 15% to 35% according to a series of previous similar studies.2,3,5,7 In addition, we found that patients with diabetes were older than those without diabetes. The prevalence of diabetes is positively associated with increasing of age and BMI in the general population.8 One might propose that older people are more likely to develop diabetes when exposed to the additional factor such as PHEO. A previous research has also reported the similar result.3 However, we didn’t found positive relationship between BMI and risk of diabetes, that is consistent with prior studies.3 There are perhaps other factors than BMI playing crucial roles in presenting of diabetes. The occurrence and development of diabetes mellitus are very complex. Factors like obesity, decreased physical exercise and inflammatory processes all have adverse influences in glucose metabolism. Besides, the loss of weight famous as a consequence of catecholamine-induced lipolysis as well as elevation in metabolic rate might obscure the relationship between BMI and diabetes.8,9 What’s more, the BMI of
Comparison of pheochromocytoma patients with and without preoperative diabetes.
Male [n (%)] Female [n (%)] Age at surgery, years Body mass index Incidentaloma [n (%)] Symptomatic [n (%)] Tumor location [n (%)] Left Right Bilateral Extra-adrenal (paraganglioma) Size on preoperative imaging, cm Catecholamines (range) Fold change catecholamines (range)
No diabetes [n Z 118]
Diabetes [n Z 67]
p-Value
49 (41.5) 69 (58.5) 43.7 14.5 21.5 4.1 32 (27.1) 86 (72.9)
22 (32.8) 45 (67.2) 53.3 9.6 22.0 2.8 17 (25.4) 50 (74.6)
0.273
39 (33.1) 61 (51.7) 5 (4.2) 13 (11.0) 5.5 2.4 5419.5 (187.0e192374.0) 15.2 (0.5e538.9)
17 (25.4) 34 (50.7) 2 (3.0) 14 (20.9) 5.1 2.0 4604.4 (204.0e6771.0) 12.9 (0.6e75.0)
<0.001 0.396 0.863
0.275
0.258 0.343
Please cite this article as: Liu Z-H et al., Will the resection of pheochromocytoma improve preoperative diabetes mellitus?, Asian Journal of Surgery, https://doi.org/10.1016/j.asjsur.2019.01.012
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Z.-H. Liu et al. Table 3
Univariate Logistic regression analysis of factors on the diabetes remission.
Male [n (%)] Female [n (%)] Age at surgery, years Body mass index Incidentaloma [n (%)] Symptomatic [n (%)] Size on preoperative imaging, cm Catecholamines (range) Fold change catecholamines (range) Tumor location [n (%)] Adrenal Extra-adrenal (paraganglioma)
Resolution [n Z 37]
No resolution [n Z 10]
p-Value
12 (32.4) 25 (67.6) 53.2 9.6 21.6 2.9 5 (13.5) 28 (86.5) 5.4 2.2 4890.9 (204.0e23228.0) 13.7 (0.6e17.5)
0 (0) 10 (100) 53.5 9.1 24.1 2.5 5 (35.7) 9 (64.3) 5.1 2.2 4248.3 (452.0e26771.0) 11.9 (1.3e75.0)
0.998
29 (78.4) 8 (21.6)
8 (80) 2 (20)
patients in this study was (21.7 3.6) which seems lower than that in the previous studies. The reason might be that we focused on Chinese patients in this study and the mean BMI of Chinese was lower than American and European people. The mean size of the PHEO was (5.3 2.2) cm. And there was no statistical difference between patients with and without diabetes about tumor size. However, Beninato et al had shown that patients with diabetes were more likely to had larger tumors; and they also revealed lager tumors were related to higher levels of catecholamine than smaller tumors.5 So, lager tumors might increase risk of diabetes by exposing patients to higher catecholamine levels. But no difference of catecholamine levels was found between patients with diabetes and those without diabetes in our study. That might be the source of the disagreement. But it is still consistent with the theory that larger tumors producing more catecholamine than smaller tumors. Furthermore, the similar result like the previous study may be obtained by expanding the sample size. As for no positive relationship was revealed between tumors characteristic risk of diabetes, there must be some other factors increasing the likelihood to present diabetes. Further study on the symptomatic patients showed that longer course of PHEO was significantly associated with the likelihood of presenting with diabetes. The known duration of PHEO might be an evaluation for the duration of exposure to the elevated catecholamine levels. And the elevated catecholamine could increase the insulinresistance and insulin-glucose homeostasis.3,10 That’s why the length of PHEO course was positively associated with the presence of diabetes.
Table 4
0.980 0.022 0.664 0.314 0.798 0.773
After removal of tumors, 37 (78.7%) patients had been with either resolution or improvement of diabetes. However, some researchers have reported that even more than 90% of patients could resolve diabetes (Table 4). A study conducted in 1984 showed us 24% (13/54) patients of PHEO with preoperative diabetes had resolution for their diabetes after surgery.11 Another study conducted in 2003 revealed that only 10% (7/68) with incomplete resection of the tumors did not resolve diabetes.3 Then, Pogorzelski et al. Published a series of 67 patients with PHEO, 31.3% (21/67) of whom were with diabetes. and they found 90% (19/21) of patients were with complete resolution of diabetes after removal of tumors.7 Finally, Beninato et al reviewed 153 patients with PHEO undergoing surgery, 23.4% (36/153) of whom accompanied with preoperative diabetes. And almost 79% (22/28) of patients with diabetes had resolution after surgery.5 Finally, we found that elevated BMI was perhaps an independent risk factor influencing the prognosis of postoperative diabetes. The prior study had shown patients with higher BMI were more likely to have diabetes independent of PHEO,12 it is likely that these patients might need continuous treatment for diabetes even after resection of PHEO and removal of the effects of the elevated catecholamine because of the high BMI. So, the BMI might be the predictive factor on the resolution or improvement of postoperative diabetes among the PHEO patients. This is consistent with what Toni Beninato had shown in the previous study.5 In addition, patients resolving diabetes were younger with larger tumors and higher preoperative catecholamine levels than those did not, although not statistically. The relationship could demonstrate that the main culprit of the abnormal glucose metabolism was the tumors
Comparison with other studies examining pheochromocytoma and diabetes.
Study
Year
Study size
Diabetes (%)
% Resolution of Diabetes
Liu et al. Beninato et al.5 Pogorzelski et al.7 La Batide-Alanore et al.3 Stenstrom et al.12
2018 2017 2014 2003 1984
185 153 67 191 54
67 36 21 68 13
78.7 78.6 90 90 100
a
(36.2) (23.4) (31.3) (35.6) (24.1)a
Patients found to have glucose intolerance preoperatively; patients with a diagnosis of diabetes were excluded.
Please cite this article as: Liu Z-H et al., Will the resection of pheochromocytoma improve preoperative diabetes mellitus?, Asian Journal of Surgery, https://doi.org/10.1016/j.asjsur.2019.01.012
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Resolution of diabetes mellitus after resection of PHEO themselves, rather than other risk factors. That’s why resection of tumors might resolve diabetes. There are several limitations to the study. First, there is perhaps selection and referral bias as the study is a retrospective review of a single-institution experience. Secondly, the comparison of patients with or without resolution of diabetes after surgery was perhaps underpowered because of the small sample size. Last but not the least, the definition of resolution of diabetes was determined by documentation of medication change, patients’ reports and normal fasting glucose levels postoperatively. It is better to make a stricter criterion through the examinations of pre- and postoperative hemoglobin A1C levels and glucose tolerance tests. However, those were not available for most of patients.
Declarations of interest None.
Acknowledgements The work is supported by the 1.3.5 project for displines of excellence, West China Hospital, Sichuan University, the National Natural Science Fund of China (8177070), the National Natural Science Fund of China (81470927) and the National Natural Science Fund of China (81800667).
References 1. Lenders JW, Duh QY, Eisenhofer G, et al. Pheochromocytoma and paraganglioma: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2014;99:1915e1942.
5 2. Chen Y, Hodin RA, Pandolfi C, et al. Hypoglycemia after resection of pheochromocytoma. Surgery. 2014;156: 1404e1408. discussion 1408-1409. 3. La Batide-Alanore A, Chatellier G, Plouin PF. Diabetes as a marker of pheochromocytoma in hypertensive patients. J Hypertens. 2003;21:1703e1707. 4. Wiesner TD, Bluher M, Windgassen M, Paschke R. Improvement of insulin sensitivity after adrenalectomy in patients with pheochromocytoma. J Clin Endocrinol Metab. 2003;88: 3632e3636. 5. Beninato T, Kluijfhout WP, Drake FT, et al. Resection of pheochromocytoma improves diabetes mellitus in the majority of patients. Ann Surg Oncol. 2017;24:1208e1213. 6. Chamberlain JJ, Rhinehart AS, Shaefer Jr CF, Neuman A. Diagnosis and management of diabetes: synopsis of the 2016 American diabetes association standards of medical care in diabetes. Ann Intern Med. 2016;164:542e552. 7. Pogorzelski R, Toutounchi S, Krajewska E, et al. The effect of surgical treatment of phaeochromocytoma on concomitant arterial hypertension and diabetes mellitus in a singlecentre retrospective study. Cent European J Urol. 2014;67: 361e365. 8. Hamaji M. Pancreatic alpha- and beta-cell function in pheochromocytoma. J Clin Endocrinol Metab. 1979;49:322e325. 9. Ratheiser KM, Brillon DJ, Campbell RG, Matthews DE. Epinephrine produces a prolonged elevation in metabolic rate in humans. Am J Clin Nutr. 1998;68:1046e1052. 10. Komada H, Hirota Y, So A, et al. Insulin secretion and insulin sensitivity before and after surgical treatment of pheochromocytoma or paraganglioma. J Clin Endocrinol Metab. 2017; 102:3400e3405. 11. Stenstrom G, Sjostrom L, Smith U. Diabetes mellitus in phaeochromocytoma. Fasting blood glucose levels before and after surgery in 60 patients with phaeochromocytoma. Acta Endocrinol. 1984;106:511e515. 12. Mokdad AH, Bowman BA, Ford ES, et al. The continuing epidemics of obesity and diabetes in the United States. Jama. 2001;286:1195e1200.
Please cite this article as: Liu Z-H et al., Will the resection of pheochromocytoma improve preoperative diabetes mellitus?, Asian Journal of Surgery, https://doi.org/10.1016/j.asjsur.2019.01.012
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Asian Journal of Surgery xxx (xxxx) xxx
Available online at www.sciencedirect.com
ScienceDirect journal homepage: www.e-asianjournalsurgery.com
ORIGINAL ARTICLE
Will the resection of pheochromocytoma improve preoperative diabetes mellitus? Zheng-Huan Liu a,1, Liang Zhou a,1, Le-De Lin a, Tao Chen b, Qing-Yao Jiang a, Zhi-Hong Liu a, Kun-Jie Wang a, Yu-Chun Zhu a,*, Hong Li a,**, Yan Ren b a Department of Urology, Institute of Urology (Laboratory of Reconstructive Urology), West China Hospital, Sichuan University, Chengdu, Sichuan, PR China b Department of Endocrinology and Metabolism, Adrenal Center, West China Hospital, Sichuan University, Guo Xue Xiang 37, Chengdu, 610000, Sichuan, PR China
Received 12 November 2018; received in revised form 8 January 2019; accepted 22 January 2019
KEYWORDS Diabetes mellitus; Development; Pheochromocytoma; Risk factor
Summary Objective: To explore the likelihood of resolution of diabetes postoperatively. Besides, we would like to determine the risk factors associated with development and prognosis of diabetes. Methods: All patients in our hospital undergoing surgical removal of pheochromocytoma (PHEO) from 10 October 2010 to 21 July 2017 were retrospectively analyzed to determine those with preoperative diabetes. Preoperatively demographic data and information on diabetes were recorded. The median follow-up was 45.2 months. Results: Finally, 67 (36.2%) patients were with diabetes among 185 patients undergoing surgery. Furthermore, 47 patients had complete follow-up. And 37 (78.7%) patients had improvement of diabetes after resection of PHEO. In details, 29 (61.7%) patients had complete resolution. Older patients were more likely to develop diabetes, and symptomatic patients with longer course of PHEO were also more susceptible to preoperative diabetes. Elevated body mass index (BMI) was a risk factor of persistent diabetes postoperatively after surgery. Conclusions: 36.2% of PHEO patients might be with preoperative diabetes mellitus. Older patients were more likely to present diabetes preoperatively. And the increasing length of PHEO course might be another risk factor on developing diabetes preoperatively. Resection of tumors improved diabetes in 78.7% of patients, with resolution in 61.7%. Patients with higher BMI might need treatment for diabetes postoperatively.
* Corresponding authors: West China Hospital, Sichuan University, Guo Xue Xiang 37, Chengdu, 610000, Sichuan, PR China. Fax: þ86 28 8542 2451. ** Corresponding authors: West China Hospital, Sichuan University, Guo Xue Xiang 37, Chengdu, 610000, Sichuan, PR China. Fax: þ86 28 8542 2451. E-mail addresses: [email protected] (Y.-C. Zhu), [email protected] (H. Li). 1 Zheng-Huan Liu and Liang Zhou have contributed equally to this work. https://doi.org/10.1016/j.asjsur.2019.01.012 1015-9584/ª 2019 Asian Surgical Association and Taiwan Robotic Surgery Association. Publishing services by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Please cite this article as: Liu Z-H et al., Will the resection of pheochromocytoma improve preoperative diabetes mellitus?, Asian Journal of Surgery, https://doi.org/10.1016/j.asjsur.2019.01.012
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Z.-H. Liu et al. ª 2019 Asian Surgical Association and Taiwan Robotic Surgery Association. Publishing services by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http:// creativecommons.org/licenses/by-nc-nd/4.0/).
1. Introduction Pheochromocytoma is a rare tumor producing catecholamine that is aroused from chromaffin cells of the adrenal medulla.1 The most well-known symptoms and signs of PHEO are hypertension, headaches, palpitations, sweating and weight loss. Besides, a range of authors have concluded that glucose intolerance and type 2 DM may be the firstly presented symptoms in approximately 50% of PHEO patients. However, there are almost no large studies, especially in China, which have talked about the long-term prognosis of such patients after surgery. In addition, 15e35% of patients with PHEO could be complicated with impaired glucose tolerance or diabetes.2,3 Not only The decreased glucose uptake, but also the increased gluconeogenesis and glycogenolysis are associated with elevated catecholamine.3 Besides, increased catecholamine may result in increased insulin resistance as well as decreased insulin secretion.4 However, the previous researches have shown quick recovery of insulin resistance and insulin secretion after resection of PHEO. Furthermore, we can even see postoperative hypoglycemia in patients without preoperative diabetes.2,4 Additionally, a recent research has shown that diabetes might occur more often in patients with large, symptomatic PHEO. Most of them could have the long-term postoperative resolution of diabetes, but patients with the higher BMI might still need treatment of diabetes after successful removal of tumors.5 However, there are little data available regarding such outcomes of patients with PHEO in China. Therefore, we performed this study to explore the prevalence of diabetes in PHEO patients and the prognosis after removal of tumors. Furthermore, we would like to identify the possible risk factors related to the prognosis of diabetes.
2. Methods All patients in West China Hospital who underwent surgical removal of PHEO from 10 October 2010 to 21 July 2017 were included in the study. And demographic data like sex, age, Body Mass Index (BMI) were all collected through the retrospective chart review. Furthermore, tumor size and the absence or presence of symptoms preoperatively were also collected. In addition, we had examined patients’ either plasma or 24-h urine normetanephrine and metanephrine concentrations measurement to confirm the biochemical diagnosis of PHEO. However, the blood and urine tests were not always performed in the same patient. Therefore, we calculated the greatest fold increase for comparison. Hereafter, the fold change will be referred to as “catecholamines”. And we define patients with chief complains including hypertension, headaches, palpitations,
sweating and weight loss as symptomatic patients. As for the PHEO course, it refers to the duration from the first time when patients complain about their symptoms. Data on blood glucose and medication use for diabetes was also collected. Patients who were complicated with diabetes were defined as those already with documentation of a confirmed diagnosis of diabetes mellitus, use of diabetes medications, abnormal hemoglobin AlC level (6.5%), evidence of multiple abnormal fasting plasma glucose level (7.0 mmol/L) or random plasma glucose level (11.1 mmol/L).6 Besides, we determined the resolution of diabetes via patients’ and clinical reports and the documentation of medication adjustments. However, patients requiring steroids after surgical removal or with inadequate follow-up were all excluded from the analysis of this study.
2.1. Statistical analysis Statistical analysis was performed via SPSS version 22.0 (IBM Corporation, Armonk, NY, USA). Chi-square tests were performed to compare the categorical variables, and the Student’s t tests or Mann-Whitney U tests were used to analyze continuous parametric and nonparametric variables, respectively. And the p-value <0.05 was defined significantly difference. Multivariate analysis was performed via binary logistic regression.
3. Results In the study, there were 185 patients who accepted resection of the PHEO. All patients’ preoperative characteristics are shown in Table 1. Among all the 185 patients, 67 (36.2%) met the criteria because of the preoperative evidence of diabetes. And all the 67 patients complicated with type II diabetes were treated with preoperative medication (either oral medication or insulin). As shown in Table 2, we found that there was no statistical difference of sex or BMI between patients with diabetes and that without diabetes. Besides, there was also no statistical difference in the size and location of the tumors, so as the proportion of tumors presented as incidentaloma rather than as symptomatic (72.9 vs. 74.6). As for the median fold change in catecholamine levels between patients with and without diabetes, there was also no significant difference (p Z 0.343). However, patients who had diabetes were significantly older than those who did not (p < 0.001). Furthermore, we found that symptomatic patients with a longer course of PHEO were more likely to develop preoperative diabetes (p Z 0.006). At last, among 67 patients with preoperative diabetes, 47 had adequate follow-up to determine the prognosis of diabetes. These patients included 22 (32.8%) men and 45
Please cite this article as: Liu Z-H et al., Will the resection of pheochromocytoma improve preoperative diabetes mellitus?, Asian Journal of Surgery, https://doi.org/10.1016/j.asjsur.2019.01.012
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Resolution of diabetes mellitus after resection of PHEO Table 1 Preoperative characteristics of patients undergoing adrenalectomy for pheochromocytoma. Patient with pheochromocytoma (n Z 185) Male [n (%)] Female [n (%)] Age at surgery, years Body mass index Incidentaloma [n (%)] Symptomatic [n (%)] Tumor location [n (%)] Left Right Bilateral Extra-adrenal (paraganglioma) Size on preoperative imaging, cm Catecholamines (range) Fold change catecholamines (range) Diabetes [n (%)] No diabetes [n (%)]
71 (38.4) 114 (61.6) 47.2 13.7 21.7 3.6 49 (26.5) 136 (73.5)
Finally, we compared the differences between patients with resolution of diabetes and those without (Table 3). The BMIs of patients with complete or partial resolution of diabetes were significantly lower than those of patients without resolution (p Z 0.022). Patients with higher preoperative catecholamine fold changes and larger tumors were also more likely to resolve their diabetes, however, the relationships were both not significant.
4. Discussion
56 (30.3) 95 (51.4) 7 (3.8) 27 (14.6) 5.3 2.2 5154.3 (187.0e192374.0) 14.4 (0.5e538.9)
67 (36.2) 118 (63.8)
(67.2%) women. The mean age of them was (53.5 9.1) years. After a median follow-up of 45.2 months (range 12.7e83.1), There were 37 (78.7%) patients with either improvement or resolution of diabetes after resection of PHEO. In details, 29 (61.7%) patients got complete resolution, which was defined as being off medication with either evidence of fasting blood glucose or patients’ reports. And 8 (17.0%) patients were reported better glucose control with the reduced dose of medication. However, ten patients did not get any improvement after surgery. They all needed the same dose of medication for their diabetes and found no improvement in glucose control during the postoperative period.
Table 2
3
In the study, we had examined all patients in West China Hospital who underwent surgical removal of PHEO from 10 October 2010 to 21 July 2017 to determine both the prevalence of preoperative diabetes and the likelihood of being with normoglycemia after removal of PHEO. Besides, we also tried to identify the patients’ demographic or tumor characteristics that might have influence on the improvement of glucose intolerance or diabetes after removal of PHEO. There were 36.2% (67/185) of the PHEO patients being with diabetes mellitus. It is higher than the incidence rate ranged from 15% to 35% according to a series of previous similar studies.2,3,5,7 In addition, we found that patients with diabetes were older than those without diabetes. The prevalence of diabetes is positively associated with increasing of age and BMI in the general population.8 One might propose that older people are more likely to develop diabetes when exposed to the additional factor such as PHEO. A previous research has also reported the similar result.3 However, we didn’t found positive relationship between BMI and risk of diabetes, that is consistent with prior studies.3 There are perhaps other factors than BMI playing crucial roles in presenting of diabetes. The occurrence and development of diabetes mellitus are very complex. Factors like obesity, decreased physical exercise and inflammatory processes all have adverse influences in glucose metabolism. Besides, the loss of weight famous as a consequence of catecholamine-induced lipolysis as well as elevation in metabolic rate might obscure the relationship between BMI and diabetes.8,9 What’s more, the BMI of
Comparison of pheochromocytoma patients with and without preoperative diabetes.
Male [n (%)] Female [n (%)] Age at surgery, years Body mass index Incidentaloma [n (%)] Symptomatic [n (%)] Tumor location [n (%)] Left Right Bilateral Extra-adrenal (paraganglioma) Size on preoperative imaging, cm Catecholamines (range) Fold change catecholamines (range)
No diabetes [n Z 118]
Diabetes [n Z 67]
p-Value
49 (41.5) 69 (58.5) 43.7 14.5 21.5 4.1 32 (27.1) 86 (72.9)
22 (32.8) 45 (67.2) 53.3 9.6 22.0 2.8 17 (25.4) 50 (74.6)
0.273
39 (33.1) 61 (51.7) 5 (4.2) 13 (11.0) 5.5 2.4 5419.5 (187.0e192374.0) 15.2 (0.5e538.9)
17 (25.4) 34 (50.7) 2 (3.0) 14 (20.9) 5.1 2.0 4604.4 (204.0e6771.0) 12.9 (0.6e75.0)
<0.001 0.396 0.863
0.275
0.258 0.343
Please cite this article as: Liu Z-H et al., Will the resection of pheochromocytoma improve preoperative diabetes mellitus?, Asian Journal of Surgery, https://doi.org/10.1016/j.asjsur.2019.01.012
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4
Z.-H. Liu et al. Table 3
Univariate Logistic regression analysis of factors on the diabetes remission.
Male [n (%)] Female [n (%)] Age at surgery, years Body mass index Incidentaloma [n (%)] Symptomatic [n (%)] Size on preoperative imaging, cm Catecholamines (range) Fold change catecholamines (range) Tumor location [n (%)] Adrenal Extra-adrenal (paraganglioma)
Resolution [n Z 37]
No resolution [n Z 10]
p-Value
12 (32.4) 25 (67.6) 53.2 9.6 21.6 2.9 5 (13.5) 28 (86.5) 5.4 2.2 4890.9 (204.0e23228.0) 13.7 (0.6e17.5)
0 (0) 10 (100) 53.5 9.1 24.1 2.5 5 (35.7) 9 (64.3) 5.1 2.2 4248.3 (452.0e26771.0) 11.9 (1.3e75.0)
0.998
29 (78.4) 8 (21.6)
8 (80) 2 (20)
patients in this study was (21.7 3.6) which seems lower than that in the previous studies. The reason might be that we focused on Chinese patients in this study and the mean BMI of Chinese was lower than American and European people. The mean size of the PHEO was (5.3 2.2) cm. And there was no statistical difference between patients with and without diabetes about tumor size. However, Beninato et al had shown that patients with diabetes were more likely to had larger tumors; and they also revealed lager tumors were related to higher levels of catecholamine than smaller tumors.5 So, lager tumors might increase risk of diabetes by exposing patients to higher catecholamine levels. But no difference of catecholamine levels was found between patients with diabetes and those without diabetes in our study. That might be the source of the disagreement. But it is still consistent with the theory that larger tumors producing more catecholamine than smaller tumors. Furthermore, the similar result like the previous study may be obtained by expanding the sample size. As for no positive relationship was revealed between tumors characteristic risk of diabetes, there must be some other factors increasing the likelihood to present diabetes. Further study on the symptomatic patients showed that longer course of PHEO was significantly associated with the likelihood of presenting with diabetes. The known duration of PHEO might be an evaluation for the duration of exposure to the elevated catecholamine levels. And the elevated catecholamine could increase the insulinresistance and insulin-glucose homeostasis.3,10 That’s why the length of PHEO course was positively associated with the presence of diabetes.
Table 4
0.980 0.022 0.664 0.314 0.798 0.773
After removal of tumors, 37 (78.7%) patients had been with either resolution or improvement of diabetes. However, some researchers have reported that even more than 90% of patients could resolve diabetes (Table 4). A study conducted in 1984 showed us 24% (13/54) patients of PHEO with preoperative diabetes had resolution for their diabetes after surgery.11 Another study conducted in 2003 revealed that only 10% (7/68) with incomplete resection of the tumors did not resolve diabetes.3 Then, Pogorzelski et al. Published a series of 67 patients with PHEO, 31.3% (21/67) of whom were with diabetes. and they found 90% (19/21) of patients were with complete resolution of diabetes after removal of tumors.7 Finally, Beninato et al reviewed 153 patients with PHEO undergoing surgery, 23.4% (36/153) of whom accompanied with preoperative diabetes. And almost 79% (22/28) of patients with diabetes had resolution after surgery.5 Finally, we found that elevated BMI was perhaps an independent risk factor influencing the prognosis of postoperative diabetes. The prior study had shown patients with higher BMI were more likely to have diabetes independent of PHEO,12 it is likely that these patients might need continuous treatment for diabetes even after resection of PHEO and removal of the effects of the elevated catecholamine because of the high BMI. So, the BMI might be the predictive factor on the resolution or improvement of postoperative diabetes among the PHEO patients. This is consistent with what Toni Beninato had shown in the previous study.5 In addition, patients resolving diabetes were younger with larger tumors and higher preoperative catecholamine levels than those did not, although not statistically. The relationship could demonstrate that the main culprit of the abnormal glucose metabolism was the tumors
Comparison with other studies examining pheochromocytoma and diabetes.
Study
Year
Study size
Diabetes (%)
% Resolution of Diabetes
Liu et al. Beninato et al.5 Pogorzelski et al.7 La Batide-Alanore et al.3 Stenstrom et al.12
2018 2017 2014 2003 1984
185 153 67 191 54
67 36 21 68 13
78.7 78.6 90 90 100
a
(36.2) (23.4) (31.3) (35.6) (24.1)a
Patients found to have glucose intolerance preoperatively; patients with a diagnosis of diabetes were excluded.
Please cite this article as: Liu Z-H et al., Will the resection of pheochromocytoma improve preoperative diabetes mellitus?, Asian Journal of Surgery, https://doi.org/10.1016/j.asjsur.2019.01.012
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Resolution of diabetes mellitus after resection of PHEO themselves, rather than other risk factors. That’s why resection of tumors might resolve diabetes. There are several limitations to the study. First, there is perhaps selection and referral bias as the study is a retrospective review of a single-institution experience. Secondly, the comparison of patients with or without resolution of diabetes after surgery was perhaps underpowered because of the small sample size. Last but not the least, the definition of resolution of diabetes was determined by documentation of medication change, patients’ reports and normal fasting glucose levels postoperatively. It is better to make a stricter criterion through the examinations of pre- and postoperative hemoglobin A1C levels and glucose tolerance tests. However, those were not available for most of patients.
Declarations of interest None.
Acknowledgements The work is supported by the 1.3.5 project for displines of excellence, West China Hospital, Sichuan University, the National Natural Science Fund of China (8177070), the National Natural Science Fund of China (81470927) and the National Natural Science Fund of China (81800667).
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5 2. Chen Y, Hodin RA, Pandolfi C, et al. Hypoglycemia after resection of pheochromocytoma. Surgery. 2014;156: 1404e1408. discussion 1408-1409. 3. La Batide-Alanore A, Chatellier G, Plouin PF. Diabetes as a marker of pheochromocytoma in hypertensive patients. J Hypertens. 2003;21:1703e1707. 4. Wiesner TD, Bluher M, Windgassen M, Paschke R. Improvement of insulin sensitivity after adrenalectomy in patients with pheochromocytoma. J Clin Endocrinol Metab. 2003;88: 3632e3636. 5. Beninato T, Kluijfhout WP, Drake FT, et al. Resection of pheochromocytoma improves diabetes mellitus in the majority of patients. Ann Surg Oncol. 2017;24:1208e1213. 6. Chamberlain JJ, Rhinehart AS, Shaefer Jr CF, Neuman A. Diagnosis and management of diabetes: synopsis of the 2016 American diabetes association standards of medical care in diabetes. Ann Intern Med. 2016;164:542e552. 7. Pogorzelski R, Toutounchi S, Krajewska E, et al. The effect of surgical treatment of phaeochromocytoma on concomitant arterial hypertension and diabetes mellitus in a singlecentre retrospective study. Cent European J Urol. 2014;67: 361e365. 8. Hamaji M. Pancreatic alpha- and beta-cell function in pheochromocytoma. J Clin Endocrinol Metab. 1979;49:322e325. 9. Ratheiser KM, Brillon DJ, Campbell RG, Matthews DE. Epinephrine produces a prolonged elevation in metabolic rate in humans. Am J Clin Nutr. 1998;68:1046e1052. 10. Komada H, Hirota Y, So A, et al. Insulin secretion and insulin sensitivity before and after surgical treatment of pheochromocytoma or paraganglioma. J Clin Endocrinol Metab. 2017; 102:3400e3405. 11. Stenstrom G, Sjostrom L, Smith U. Diabetes mellitus in phaeochromocytoma. Fasting blood glucose levels before and after surgery in 60 patients with phaeochromocytoma. Acta Endocrinol. 1984;106:511e515. 12. Mokdad AH, Bowman BA, Ford ES, et al. The continuing epidemics of obesity and diabetes in the United States. Jama. 2001;286:1195e1200.
Please cite this article as: Liu Z-H et al., Will the resection of pheochromocytoma improve preoperative diabetes mellitus?, Asian Journal of Surgery, https://doi.org/10.1016/j.asjsur.2019.01.012