Change of Computed Tomography-Based Body Composition after Adrenalectomy in Patients with Pheochromocytoma
by
Yousun Ko
1, 
Heeryoel Jeong
2,
Seungwoo Khang
2,
Jeongjin Lee
2,
Kyung Won Kim
3,* and
Beom-Jun Kim
4,* 1
Biomedical Research Center, Asan Institute for Life Sciences, Asan Medical Center, Seoul 05505, Korea
2
School of Computer Science and Engineering, Soongsil University, Seoul 06978, Korea
3
Department of Radiology and Research Institute of Radiology, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea
4
Division of Endocrinology and Metabolism, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea
*
Authors to whom correspondence should be addressed.
Cancers 2022, 14(8), 1967; https://doi.org/10.3390/cancers14081967
Submission received: 21 February 2022
/
Revised: 31 March 2022
/
Accepted: 11 April 2022
/
Published: 13 April 2022
(This article belongs to the Special Issue Management and Treatment of Endocrine Tumors)
Abstract
:Simple Summary
Pheochromocytoma is regarded as a good human model for investigating the impact of sympathetic hyperactivity on various pathologic conditions. To determine the influence of catecholamine excess on human body composition, we compared computed tomography (CT)-based fat and skeletal muscle indices over time in a large patient population with histologically confirmed pheochromocytoma who underwent surgery. We observed considerable elevation in CT-measured visceral fat area and subcutaneous fat area, and the prevalence of visceral obesity after adrenalectomy in patients with pheochromocytoma. In contrast, there were no changes in skeletal muscle area, skeletal muscle index, and prevalence of sarcopenia. Furthermore, we observed that the severity of catecholamine excess was associated with a higher increase, especially in the subcutaneous fat area after surgery. These data provide important clinical evidence that sympathetic hyperactivity contributes to lipolysis in visceral and subcutaneous adipose tissues, whereas its impact on human skeletal muscle remains undetermined.
Abstract
Despite the potential biological importance of the sympathetic nervous system on fat and skeletal muscle metabolism in animal and in vitro studies, its relevance in humans remains undetermined. To clarify the influence of catecholamine excess on human body composition, we performed a retrospective longitudinal cohort study including 313 consecutive patients with histologically confirmed pheochromocytoma who underwent repeat abdominal computed tomography (CT) scans before and after adrenalectomy. Changes in CT-determined visceral fat area (VFA), subcutaneous fat area (SFA), skeletal muscle area (SMA), and skeletal muscle index (SMI) were measured at the level of the third lumbar vertebra. The mean age of all patients was 50.6 ± 13.6 years, and 171/313 (54.6%) were women. The median follow-up duration for repeat CTs was 25.0 months. VFA and SFA were 14.5% and 15.8% higher, respectively (both p < 0.001), after adrenalectomy, whereas SMA and SMI remained unchanged. Similarly, patients with visceral obesity significantly increased from 103 (32.9%) at baseline to 138 (44.1%) following surgery (p < 0.001); however, the prevalence of sarcopenia was unchanged. This study provides important clinical evidence that sympathetic hyperactivity can contribute to lipolysis in visceral and subcutaneous adipose tissues, but its impact on human skeletal muscle is unclear.
1. Introduction
Pheochromocytoma and paraganglioma are catecholamine-secreting neuroendocrine tumors arising from chromaffin cells of the adrenal medulla and sympathetic paravertebral ganglia, respectively [1]. In addition to the classic triad of symptoms including episodic palpitations, sweating, and headache, catecholamine overproduction is responsible for many cardiovascular and metabolic alterations in patients with pheochromocytoma [2]. For example, a recent study reported that elevated cholesterol levels were improved by surgical resection in patients with pheochromocytoma [3]. Catecholamines are key neurotransmitters of the sympathetic nervous system (SNS), and they exert their biological effects through adrenergic receptors (ARs). Pheochromocytoma is therefore regarded as a good human model for investigating the impact of sympathetic hyperactivity on various pathologic conditions [4,5].
In an era wherein sedentary lifestyles and high-fat diets are common, obesity and sarcopenia are becoming increasingly relevant to public health [6,7,8]; thus, research on critical modulators affecting body composition is actively pursued. Interestingly, adipose tissue and skeletal muscle express abundant ARs [9,10,11,12], and accumulating evidence from in vitro and animal studies indicates clear implications for SNS in fat and muscle metabolism [12,13,14,15]. Therefore, research has been conducted to examine the effects of catecholamine excess on body composition in patients with pheochromocytoma. However, these studies did not consider fat and muscle together and had various limitations, including small sample sizes and cross-sectional design [16,17,18,19]. Large-scale longitudinal investigations are thus required to thoroughly elucidate the causal consequences of sympathetic overstimulation on body composition in humans.
A single-slice computed tomography (CT) scan at the level of the third lumbar vertebra (L3) is a well-established tool to assess the tissue volumes of subcutaneous and visceral fat and skeletal muscle [20,21,22]. Moreover, a fully convolutional network-based segmentation system of CT images has greatly improved its accuracy and reproducibility [23]. Importantly, unless contraindicated, all patients with pheochromocytoma should undergo adrenalectomy or mass excision, and abdomen CT should be taken before and after surgery to screen for metastasis and recurrence, respectively. Therefore, to determine the influence of SNS on human body composition, we compared CT-based fat and skeletal muscle indices over time in a large patient population with pheochromocytoma who underwent surgery and investigated the associations of catecholamine metabolites with these parameters.
2. Materials and Methods
2.1. Study Participants
Between January 2005 and December 2019, 441 patients were histologically confirmed with pheochromocytoma or paraganglioma among those who underwent adrenalectomy or mass excision at the Asan Medical Center ((AMC) Seoul, Korea). Of these, 313 patients had abdominal CT scans before and 3 to 48 months after surgery and were subsequently included in this study. This study was approved by the Institutional Review Board of AMC (No. 2021-0208), and the requirement for patient informed consent was waived given the retrospective nature of the study. Data were obtained from the Clinical Data Repository system, electronic medical records, and the radiology picture archiving and communication system at AMC.
2.2. Laboratory Measurements
Plasma fractionated metanephrine levels were measured by liquid chromatography–tandem mass spectrometry analysis using a Xevo-TQs tandem mass spectrometer (Waters Corporation, Milford, MA, USA) and an ACQUITY UPLC column (2.1 × 50 mm BEH Amide 1.7 μm; Waters Corporation). The limit of detection and quantitation were 0.06 nmol/L and 0.08 nmol/L, respectively. The reference ranges for plasma metanephrine and normetanephrine were less than 0.5 nmol/L and 0.9 nmol/L, respectively. Twenty-four-hour urine fractionated metanephrine levels were measured with an HPLC assay using a commercially available kit (Chromsystems, Munich, Germany) on an Agilent 1100 HPLC System (Agilent Technologies, Santa Clara, CA, USA). The lower limit of detection for the kit was 5–11 μg/L, and the intra- and inter-assay CVs were <3.0% and <4.4%, respectively. The reference ranges for urine metanephrine and normetanephrine were less than 341 μg/day and 444 μg/day, respectively.
2.3. CT Image Acquisition
All CTs were performed using a 16-channel or higher (LightSpeed VCT and Discovery CT 750 HD, GE Healthcare, Milwaukee, WI, USA; Somatom Definition AS+, and Somatom Definition Edge, Siemens Medical Solution, Erlangen, Germany) CT scanner with the following parameters: tube voltage, 120 kVp; effective tube current, 50–400 mA (AutomA or SmartmA; GE Healthcare) or 200 reference mAs (care dose 4D; Siemens Medical Solution); field of view, 30–40 cm; section thickness, 5 mm. Contrast agents were administered at a rate of 3–4 mL/s, and CT images were obtained, including the portal venous phase (120 s after contrast agent injection) in the craniocaudal direction.
2.4. Analysis of CT Images and BoAdy Composition
Body morphometry on CT was evaluated with an artificial intelligence software (AID-UTM, iAID Inc., Seoul, Korea), a fully automatic deep learning system for L3 selection and body composition assessment, as detailed in Ha et al.’s work [24]. The software uses a YOLOv3-based algorithm for automatic L3 inferior endplate level selection and a fully convolutional network (FCN) for segmentation of abdominal muscle and fat [23,25]. Selected L3-level CT images were automatically segmented to generate a boundary of total abdominal muscles, and the abdominal muscle and fat areas were measured. Next, experienced operators (Y.K and K.W.K) assessed the quality of the muscle segmentation in all images. The skeletal muscle area (SMA), including all muscles on the selected axial images (i.e., psoas, paraspinal, transversus abdominis, rectus abdominis, quadratus lumborum, and internal and external obliques) was demarcated using predetermined thresholds of −29 to +150 Hounsfield units. The visceral fat area (VFA) and the subcutaneous fat area (SFA) were also demarcated using fat tissue thresholds of −190 to −30 Hounsfield units.
2.5. Definition of Visceral Obesity and Sarcopenia
Visceral obesity was defined as a VFA >100 cm2 based on the Japan Society of the Study of Obesity guidelines [26]. The skeletal muscle index (SMI) was calculated as the SMA divided by the height squared in meters (cm2/m2). Sarcopenia was defined using a diagnostic cutoff based on a T-score of −2.0 in healthy Korean patients [27]. The number of individuals with sarcopenia was calculated as an SMI at L3 of <39.8 cm2/m2 in men and <28.4 cm2/m2 in women or as an SMA at L3 of <119.3 cm2 in men and <74.2 cm2 in women.
2.6. Statistical Analysis
Continuous variables are reported as mean ± standard deviation (SD) and categorical variables as numbers and percentages unless otherwise specified. VFA, SFA, SMA, and SMI before and after adrenalectomy were compared using paired t-tests, whereas the changes of catecholamine metabolites were assessed with the Wilcoxon signed-rank test. The prevalence of visceral obesity and sarcopenia based on SMA and SMI at baseline and follow-up was compared using McNemar’s test for paired proportions. To determine the associations of baseline catecholamine metabolites with changes in CT-determined body composition before and after adrenalectomy, multivariable linear regression analyses were performed after adjustment for age, sex, body mass index (BMI), and follow up duration. The associations between changes in catecholamine metabolites and changes in CT-determined body composition after surgery were also evaluated by multivariable linear regression analyses. A two-sided p-value of <0.05 was considered statistically significant. All statistical analyses were performed using SPSS for Windows version 21.0 (IBM Corp.: Armonk, NY, USA) and R version 4.1.0 (R Foundation for Statistical Computing, Vienna, Austria).
3. Results
The baseline characteristics of 313 patients with pheochromocytoma in the study are listed in Table 1. The mean age was 50.6 ± 13.6 years (range, 12–92), and 171 (54.6%) were women. Among the 313 patients, 20 (6.4%) and 29 (9.3%) had genetic mutations and metastatic or bilateral lesions, respectively. Laparoscopic surgery was performed on 215 (68.7%) patients, while the remaining patients underwent open surgery. A median follow-up duration for repeat CTs was 25 months (range, 3–48).
Changes in catecholamine metabolites and CT-determined body composition before and after adrenalectomy were compared across all participants (Table 2 and Figure 1). As expected, metanephrine and normetanephrine levels in plasma and urine significantly decreased after adrenalectomy (all p < 0.001) and 96.2% (301 out of 313) had fractionated metanephrine levels in plasma and urine below the upper limit of the reference ranges. Notably, VFA and SFA significantly increased by 14.5% and 15.8%, respectively (both p < 0.001), after adrenalectomy. However, there was no difference in muscle parameters, including SMA and SMI, after surgery in patients with pheochromocytoma. Representative CT images measuring body composition are presented in Figure 2.
The prevalence of CT-determined visceral obesity and sarcopenia was compared between the baseline and the median follow-up period of 25 months following adrenalectomy (Figure 3). Among the total 313 participants, those with visceral obesity significantly increased from 103 (32.9%) at baseline to 138 (44.1%) after surgery (p < 0.001). In contrast, there was no difference in the prevalence of sarcopenia based on SMA and SMI before and after adrenalectomy.
The associations of baseline catecholamine metabolites with changes in CT-based body composition following adrenalectomy were analyzed (Table 3). In an unadjusted model, higher levels of plasma metanephrine and urine normetanephrine at baseline were related to greater increases in SFA, and their statistical significance remained after adjusting for age, sex, BMI, and follow-up duration (p = 0.001 to 0.031). However, no baseline catecholamine metabolites were associated with changes in SMA and SMI in repeat CT scans, regardless of adjustment models.
We then examined the relationships between changes in catecholamine metabolites and CT-determined body composition before and after adrenalectomy in patients with pheochromocytoma (Table 4). In the unadjusted and multivariable-adjusted models, higher reductions of plasma metanephrine and urine normetanephrine following adrenalectomy were associated with greater increases in SFA (p = 0.001 to 0.040). Among muscle parameters, only a greater reduction of urine normetanephrine after adrenalectomy was associated with an increase in SMI after adjusting for confounding factors (p = 0.042).
4. Discussion
Pheochromocytoma is a rare neoplasm, probably occurring in less than 0.2 percent of patients with hypertension, and commonly produces one or more catecholamines [1,2]. Although much research on metabolic alterations in these patients has been conducted to investigate the effects of sympathetic overstimulation on human homeostasis [3,28,29], there has been a paucity of thorough clinical studies in terms of physical changes. The presented study on patients with histologically confirmed pheochromocytoma assessed changes in CT-based body composition after adrenalectomy and found that VFA and SFA, but not skeletal muscle parameters, were markedly higher after surgery. Similarly, the prevalence of visceral obesity significantly increased, whereas the prevalence of sarcopenia remained unchanged after adrenalectomy. To the best of our knowledge, this is the most extensive longitudinal study on body composition, including both fat and muscle, in patients with pheochromocytoma.
Experimental research suggests that SNS may influence fat metabolism through various mechanisms. Among three β-ARs present in human adipocytes, β1 and β2 are the most functionally active [11,12]. Catecholamines bound to these receptors sequentially activate adenylyl cyclase and cAMP-protein kinase A (PKA), then stimulate hormone-sensitive lipase, which degrades triglycerides to glycerol and fatty acids [12,30]. Activation of adipose triglyceride lipase may also contribute to catecholamine-induced lipolysis [31,32]. Furthermore, the β-AR-uncoupling protein 1 (UCP1) system regulates brown adipose tissue (BAT), which converts calories into heat in both rodents and humans [16,33], and BAT hyperactivity by catecholamine excess can lead to the burning of large amounts of fat via oxidation in mitochondria [15]. These data support the direct effects of sympathetic overstimulation on lipolysis. Among human studies, Okamura et al. [18] showed that fat mass in patients with pheochromocytoma was significantly increased after adrenalectomy. Although their study is among the first to implicate the importance of SNS on human adipose tissue, drawing finite conclusions from the data is challenging due to the small sample size of only 43 patients. We overcame this limitation in the present study by comparing body composition changes after surgery in a large cohort of more than 300 patients with pheochromocytoma and additionally reported the associations between baseline level, or delta change, of catecholamine metabolites and fat parameters. Consequently, we have provided more convincing evidence for lipolysis by sympathetic hyperactivity in humans.
The adipose tissue lining internal organs is called visceral fat, whereas that beneath the skin is termed subcutaneous fat. Interestingly, the degree of catecholamine-induced lipolysis and hormone-sensitive lipase activity in rats may differ according to its location [34]. The expression level of ARs also could vary according to the type of adipose tissue [35,36]. Therefore, sympathetic activity may have different effects on the metabolic processes for visceral and subcutaneous adipocytes via distinct ARs in humans. Indeed, our study showed that the increase in SFA (15.8%) after adrenalectomy was greater than that of VFA (14.5%) and that catecholamine metabolite levels were primarily related to SFA rather than VFA. Further research is necessary to elucidate how SNS influences visceral and subcutaneous fat through different mechanisms in humans.
Muscle metabolism appears to be affected by favorable and adverse catecholamine activity. In detail, β2-AR stimulation may promote skeletal muscle hypertrophy via the up-regulation of PKA or phosphoinositol 3-kinase (PI3K)-AKT signals and resultant muscle anabolic pathways [10,14,37]. Chronic activation of α-AR, on the other hand, may cause increased oxidative stress and decreased blood flow because of vasoconstriction, causing muscle wasting [10,13,38]. As a result, the involvement of catecholamines in muscle homeostasis is complex, and their net effects remain unclear, particularly in human muscle health. In this regard, one of the most notable findings of our study was that SMA, SMI and the prevalence of sarcopenia were not affected by adrenalectomy. Given that this is the first longitudinal study to investigate changes of muscle phenotypes in pheochromocytoma, current evidence cannot support the critical role of sympathetic activity, at least, in human skeletal muscle.
The current study has major strengths in its longitudinal design, comparing changes in body composition, including both fat and muscle using a well-validated deep learning based CT scan. Furthermore, we consecutively enrolled all patients with histologically confirmed pheochromocytoma or paraganglioma to minimize selection bias. Several potential limitations should be considered when interpreting our results despite these strengths. First, non-functional adrenal tumors do not require surgery unless they are large or suspected of malignancy. We therefore had no available controls and comparative analysis was not possible. Second, although we considered key confounders in the analyses, we cannot exclude the possibility that the observed findings were attributed to uncontrolled factors that affect body composition, such as exercise, serum 25-hydroxyvitamin D level, or medications. Third, the follow-up duration for repeat CT scans was considered in the multivariable analyses; nevertheless, its various timing, ranging from 3 to 48 months, may affect the results. Lastly, our study population was exclusively Korean, so we cannot determine the global applicability of these data.
5. Conclusions
We observed considerable elevation in CT-measured VFA and SFA, and the prevalence of visceral obesity after adrenalectomy in patients with pheochromocytoma. In contrast, there were no changes in SMA and SMI, or the prevalence of sarcopenia. Furthermore, we observed that the severity of catecholamine excess was associated with a higher increase, especially in SFA after surgery. These data provide important clinical evidence that sympathetic hyperactivity contributes to lipolysis in visceral and subcutaneous adipose tissues, whereas its impact on human skeletal muscle remains undetermined. These findings further suggest that when discussing postoperative expectations in patients with pheochromocytoma, it is necessary to sufficiently explain changes in not only metabolic but also physical aspects.
Author Contributions
Conceptualization, K.W.K. and B.-J.K.; Data Acquisition, Y.K., K.W.K., and B.-J.K.; Data Analysis and Interpretation, Y.K., H.J., S.K., J.L., K.W.K. and B.-J.K.; Funding Acquisition, K.W.K. and B.-J.K.; Drafting of Manuscript, Y.K., K.W.K., and B.-J.K. All authors have read and agreed to the published version of the manuscript.
Funding
This study was supported by grants from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (grant no.: HI18C1216), and from the Asan Institute for Life Science, Asan Medical Center, Seoul, Republic of Korea (grant no.: 2021IT0003).
Institutional Review Board Statement
The study protocol conformed to the Ethical Principles for Medical Research Involving Human Subjects, as defined by the Declaration of Helsinki, and was approved by the AMC institutional review board (No. 2021-0208).
Informed Consent Statement
The requirement for patient informed consent was waived given the retrospective nature of the study.
Data Availability Statement
The datasets analyzed during the current study are available from the corresponding author on reasonable request.
Conflicts of Interest
The authors declare no conflict of interest.
References
- Kim, J.H.; Moon, H.; Noh, J.; Lee, J.; Kim, S.G. Epidemiology and Prognosis of Pheochromocytoma/Paraganglioma in Korea: A Nationwide Study Based on the National Health Insurance Service. Endocrinol. Metab. 2020, 35, 157–164. [Google Scholar] [CrossRef] [PubMed]
- Ku, E.J.; Kim, K.J.; Kim, J.H.; Kim, M.K.; Ahn, C.H.; Lee, K.A.; Lee, S.H.; Lee, Y.-B.; Park, K.H.; Choi, Y.M.; et al. Diagnosis for Pheochromocytoma and Paraganglioma: A Joint Position Statement of the Korean Pheochromocytoma and Paraganglioma Task Force. Endocrinol. Metab. 2021, 36, 322–338. [Google Scholar] [CrossRef] [PubMed]
- Good, M.L.; Malekzadeh, P.; Ruff, S.M.; Gupta, S.; Copeland, A.; Pacak, K.; Nilubol, N.; Kebebew, E.; Patel, D. Surgical Resection of Pheochromocytomas and Paragangliomas is Associated with Lower Cholesterol Levels. World J. Surg. 2020, 44, 552–560. [Google Scholar] [CrossRef] [PubMed]
- Kim, B.-J.; Lee, S.H.; Koh, J.-M. Bone Health in Adrenal Disorders. Endocrinol. Metab. 2018, 33, 1–8. [Google Scholar] [CrossRef] [PubMed]
- Kim, B.-J.; Kwak, M.K.; Ahn, S.H.; Kim, H.; Lee, S.H.; Song, K.-H.; Suh, S.; Kim, J.H.; Koh, J.-M. Lower Bone Mass and Higher Bone Resorption in Pheochromocytoma: Importance of Sympathetic Activity on Human Bone. J. Clin. Endocrinol. Metab. 2017, 102, 2711–2718. [Google Scholar] [CrossRef] [Green Version]
- Roh, E.; Choi, K.M. Health Consequences of Sarcopenic Obesity: A Narrative Review. Front. Endocrinol. 2020, 11, 332. [Google Scholar] [CrossRef] [PubMed]
- Dao, T.; Green, A.E.; Kim, Y.A.; Bae, S.-J.; Ha, K.-T.; Gariani, K.; Lee, M.-R.; Menzies, K.J.; Ryu, D. Sarcopenia and Muscle Aging: A Brief Overview. Endocrinol. Metab. 2020, 35, 716–732. [Google Scholar] [CrossRef] [PubMed]
- Yoo, J.-I.; Lee, K.-H.; Choi, Y.; Lee, J.; Park, Y.-G. Poor Dietary Protein Intake in Elderly Population with Sarcopenia and Osteosar-copenia: A Nationwide Population-Based Study. J. Bone. Metab. 2020, 27, 301–310. [Google Scholar] [CrossRef]
- Kim, Y.S.; Sainz, R.D.; Molenaar, P.; Summers, R.J. Characterization of beta 1- and beta 2-adrenoceptors in rat skeletal muscles. Biochem. Pharmacol. 1991, 42, 1783–1789. [Google Scholar] [CrossRef]
- Lynch, G.S.; Ryall, J.G. Role of beta-adrenoceptor signaling in skeletal muscle: Implications for muscle wasting and disease. Physiol. Rev. 2008, 88, 729–767. [Google Scholar] [CrossRef] [Green Version]
- Barbe, P.; Millet, L.; Galitzky, J.; Lafontan, M.; Berlan, M. In situ assessment of the role of the beta 1-, beta 2- and beta 3-adrenoceptors in the control of lipolysis and nutritive blood flow in human subcutaneous adipose tissue. Br. J. Pharmacol. 1996, 117, 907–913. [Google Scholar] [CrossRef] [PubMed]
- Jocken, J.W.; Blaak, E.E. Catecholamine-induced lipolysis in adipose tissue and skeletal muscle in obesity. Physiol. Behav. 2008, 94, 219–230. [Google Scholar] [CrossRef] [PubMed]
- McElligott, M.A.; Barreto, A.; Lee-Yuh, C. Effect of continuous and intermittent clenbuterol feeding on rat growth rate and muscle. Comp. Biochem. Physiol. Part C Comp. Pharmacol. 1989, 92, 135–138. [Google Scholar] [CrossRef]
- Navegantes, L.C.C.; Resano, N.M.Z.; Migliorini, R.H.; Kettelhut, Í.C. Role of adrenoceptors and cAMP on the catecholamine-induced inhibition of proteolysis in rat skeletal muscle. Am. J. Physiol. Metab. 2000, 279, E663–E668. [Google Scholar] [CrossRef] [PubMed]
- Bahler, L.; Molenaars, R.; Verberne, H.; Holleman, F. Role of the autonomic nervous system in activation of human brown adipose tissue: A review of the literature. Diabetes Metab. 2015, 41, 437–445. [Google Scholar] [CrossRef] [PubMed]
- Wang, Q.; Zhang, M.; Ning, G.; Gu, W.; Su, T.; Xu, M.; Li, B.; Wang, W. Brown Adipose Tissue in Humans Is Activated by Elevated Plasma Catecholamines Levels and Is Inversely Related to Central Obesity. PLoS ONE 2011, 6, e21006. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Lee, S.H.; Kwak, M.K.; Ahn, S.H.; Kim, H.; Cho, Y.Y.; Suh, S.; Song, K.-H.; Koh, J.-M.; Kim, J.H.; Kim, B.-J. Change of skeletal muscle mass in patients with pheochromocytoma. J. Bone Miner. Metab. 2018, 37, 694–702. [Google Scholar] [CrossRef]
- Okamura, T.; Nakajima, Y.; Satoh, T.; Hashimoto, K.; Sapkota, S.; Yamada, E.; Okada, S.; Fukuda, J.; Higuchi, T.; Tsushima, Y.; et al. Changes in visceral and subcutaneous fat mass in patients with pheochromocytoma. Metabolism 2015, 64, 706–712. [Google Scholar] [CrossRef]
- Petrák, O.; Haluzíková, D.; Kaválková, P.; Štrauch, B.; Rosa, J.; Holaj, R.; Brabcová, V.A.; Michalsky, D.; Haluzík, M.; Zelinka, T.; et al. Changes in energy metabolism in pheochromocytoma. J. Clin. Endocrinol. Metab. 2013, 98, 1651–1658. [Google Scholar] [CrossRef] [Green Version]
- Jones, K.I.; Doleman, B.; Scott, S.; Lund, J.; Williams, J.P. Simple psoas cross-sectional area measurement is a quick and easy method to assess sarcopenia and predicts major surgical complications. Color. Dis. 2015, 17, O20–O26. [Google Scholar] [CrossRef] [Green Version]
- Mourtzakis, M.; Prado, C.M.; Lieffers, J.R.; Reiman, T.; McCargar, L.J.; Baracos, V.E. A practical and precise approach to quantification of body composition in cancer patients using computed tomography images acquired during routine care. Appl. Physiol. Nutr. Metab. 2008, 33, 997–1006. [Google Scholar] [CrossRef] [PubMed]
- Shuster, A.; Patlas, M.; Pinthus, J.H.; Mourtzakis, M. The clinical importance of visceral adiposity: A critical review of methods for visceral adipose tissue analysis. Br. J. Radiol. 2012, 85, 1–10. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Park, H.J.; Shin, Y.; Park, J.; Kim, H.; Lee, I.S.; Seo, D.-W.; Huh, J.; Lee, T.Y.; Park, T.; Lee, J.; et al. Development and Validation of a Deep Learning System for Segmentation of Abdominal Muscle and Fat on Computed Tomography. Korean J. Radiol. 2020, 21, 88–100. [Google Scholar] [CrossRef] [PubMed]
- Ha, J.; Park, T.; Kim, H.-K.; Shin, Y.; Ko, Y.; Kim, D.W.; Sung, Y.S.; Lee, J.; Ham, S.J.; Khang, S.; et al. Development of a fully automatic deep learning system for L3 selection and body composition assessment on computed tomography. Sci. Rep. 2021, 11, 21656. [Google Scholar] [CrossRef] [PubMed]
- Kim, D.W.; Kim, K.W.; Ko, Y.; Park, T.; Khang, S.; Jeong, H.; Koo, K.; Lee, J.; Kim, H.-K.; Ha, J.; et al. Assessment of Myosteatosis on Computed Tomography by Automatic Generation of a Muscle Quality Map Using a Web-Based Toolkit: Feasibility Study. JMIR Med. Inform. 2020, 8, e23049. [Google Scholar] [CrossRef]
- Examination Committee of Criteria for ‘Obesity Disease’ in Japan; Japan Society for the Study of Obesity. New criteria for ’obesity disease’ in Japan. Circ. J. 2002, 66, 987–992. [Google Scholar] [CrossRef] [Green Version]
- Kim, E.H.; Kim, K.W.; Shin, Y.; Lee, J.; Ko, Y.; Kim, Y.-J.; Lee, M.J.; Bae, S.-J.; Park, S.W.; Choe, J.; et al. Reference Data and T-Scores of Lumbar Skeletal Muscle Area and Its Skeletal Muscle Indices Measured by CT Scan in a Healthy Korean Population. J. Gerontol. Ser. A 2021, 76, 265–271. [Google Scholar] [CrossRef]
- Wiesner, T.D.; Blüher, M.; Windgassen, M.; Paschke, R. Improvement of Insulin Sensitivity after Adrenalectomy in Patients with Pheochromocytoma. J. Clin. Endocrinol. Metab. 2003, 88, 3632–3636. [Google Scholar] [CrossRef] [PubMed]
- Resmini, E.; Minuto, F.; Colao, A.; Ferone, D. Secondary diabetes associated with principal endocrinopathies: The impact of new treatment modalities. Geol. Rundsch. 2009, 46, 85–95. [Google Scholar] [CrossRef]
- Steinberg, D.; Huttunen, J.K. The role of cyclic AMP in activation of hormone-sensitive lipase of adipose tissue. Adv. Cycl. Nucleotide Res. 1972, 1, 47–62. [Google Scholar]
- Langin, D.; Dicker, A.; Tavernier, G.; Hoffstedt, J.; Mairal, A.; Rydén, M.; Arner, E.; Sicard, A.; Jenkins, C.M.; Viguerie, N.; et al. Adipocyte Lipases and Defect of Lipolysis in Human Obesity. Diabetes 2005, 54, 3190–3197. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Rydén, M.; Jocken, J.; van Harmelen, V.; Dicker, A.; Hoffstedt, J.; Wirén, M.; Blomqvist, L.; Mairal, A.; Langin, D.; Blaak, E.; et al. Comparative studies of the role of hormone-sensitive lipase and adipose triglyceride lipase in human fat cell lipolysis. Am. J. Physiol. Metab. 2007, 292, E1847–E1855. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Cannon, B.; Nedergaard, J. Brown Adipose Tissue: Function and Physiological Significance. Physiol. Rev. 2004, 84, 277–359. [Google Scholar] [CrossRef]
- Morimoto, C.; Tsujita, T.; Okuda, H. Norepinephrine-induced lipolysis in rat fat cells from visceral and subcutaneous sites: Role of hormone-sensitive lipase and lipid droplets. J. Lipid Res. 1997, 38, 132–138. [Google Scholar] [CrossRef]
- Reynisdottir, S.; Wahrenberg, H.; Carlström, K.; Rössner, S.; Arner, P. Catecholamine resistance in fat cells of women with up-per-body obesity due to decreased expression of beta 2-adrenoceptors. Diabetologia 1994, 37, 428–435. [Google Scholar] [CrossRef]
- Hoffstedt, J.; Arner, P.; Hellers, G.; Lönnqvist, F. Variation in adrenergic regulation of lipolysis between omental and subcutaneous adipocytes from obese and non-obese men. J. Lipid Res. 1997, 38, 795–804. [Google Scholar] [CrossRef]
- Kline, W.O.; Panaro, F.J.; Yang, H.; Bodine, S.C. Rapamycin inhibits the growth and muscle-sparing effects of clenbuterol. J. Appl. Physiol. 2007, 102, 740–747. [Google Scholar] [CrossRef] [Green Version]
- Bacurau, A.V.N.; Jardim, M.A.; Ferreira, J.C.B.; Bechara, L.R.G.; Bueno, C.R.; Alba-Loureiro, T.C.; Negrao, C.E.; Casarini, D.E.; Curi, R.; Ramires, P.R.; et al. Sympathetic hyperactivity differentially affects skeletal muscle mass in developing heart failure: Role of exercise training. J. Appl. Physiol. 2009, 106, 1631–1640. [Google Scholar] [CrossRef] [Green Version]
Figure 1.
Changes in computed tomography-determined body compositions including visceral fat area (A), subcutaneous fat area (B), skeletal muscle area (C), and skeletal muscle index (D), before and after adrenalectomy in patients with pheochromocytoma. All p-values were calculated using the paired t-test or Wilcoxon signed-rank test, as appropriate. ADX, adrenalectomy.
Figure 1.
Changes in computed tomography-determined body compositions including visceral fat area (A), subcutaneous fat area (B), skeletal muscle area (C), and skeletal muscle index (D), before and after adrenalectomy in patients with pheochromocytoma. All p-values were calculated using the paired t-test or Wilcoxon signed-rank test, as appropriate. ADX, adrenalectomy.
Figure 2.
Representative image for body composition measurement using automated artificial intelligence software AID-UTM (iAID inc, Seoul, Korea). Subcutaneous fat area (SFA; brown) and visceral fat area (VFA; purple) increased following adrenalectomy (ADX), whereas skeletal muscle area (SMA; red) statistically remained unchanged. These findings were observed in 266 out of 313 patients (85.0%).
Figure 2.
Representative image for body composition measurement using automated artificial intelligence software AID-UTM (iAID inc, Seoul, Korea). Subcutaneous fat area (SFA; brown) and visceral fat area (VFA; purple) increased following adrenalectomy (ADX), whereas skeletal muscle area (SMA; red) statistically remained unchanged. These findings were observed in 266 out of 313 patients (85.0%).
Figure 3.
Changes in the prevalence of computed tomography-determined visceral obesity (A), sarcopenia based on skeletal muscle area (B), and skeletal muscle index (C) before and after adrenalectomy in patients with pheochromocytoma. All p-values were calculated using McNemar’s test for paired proportions. ADX, adrenalectomy; SMA, skeletal muscle area; SMI, skeletal muscle index.
Figure 3.
Changes in the prevalence of computed tomography-determined visceral obesity (A), sarcopenia based on skeletal muscle area (B), and skeletal muscle index (C) before and after adrenalectomy in patients with pheochromocytoma. All p-values were calculated using McNemar’s test for paired proportions. ADX, adrenalectomy; SMA, skeletal muscle area; SMI, skeletal muscle index.
Table 1.
Baseline characteristics of study participants.
| Variables | Participants (n = 313) | Variables | Participants (n = 313) |
|---|---|---|---|
| Age (years) | 50.6 ± 13.6 | Systolic BP (mmHg) | 127.4 ± 19.2 |
| Women, n (%) | 171 (54.6) | Diastolic BP (mmHg) | 79.0 ± 11.9 |
| Height (cm) | 162.2 ± 8.4 | Calcium (mg/dL) | 9.1 ± 0.5 |
| Weight (kg) | 63.4 ± 11.4 | Phosphorus (mg/dL) | 3.8 ± 0.7 |
| Body mass index (kg/m2) | 24.0 ± 3.5 | Glucose (mg/dL) | 118.5 ± 36.5 |
| Genetic mutations, n (%) | 20 (6.4) | HbA1c (%) | 6.1 ± 0.9 |
| Metastatic or bilateral lesion, n (%) | 29 (9.3) | Creatinine (mg/dL) | 0.79 ± 0.19 |
| Type of operation, n (%) | Total cholesterol (mg/dL) | 184.0 ± 37.3 | |
| Laparoscopic | 215 (68.7) | AST (IU/L) | 21.9 ± 8.1 |
| Open | 98 (31.3) | ALT (IU/L) | 22.3 ± 14.2 |
Continuous variables are reported as mean ± standard deviation and categorical variables as numbers and percentages. ALT, alanine aminotransferase; AST, aspartate aminotransferase; BP, blood pressure; HbA1c, glycated hemoglobin.
Table 2.
Changes in computed tomography-determined body composition and catecholamine metabolites before and after adrenalectomy in patients with pheochromocytoma.
Table 2.
Changes in computed tomography-determined body composition and catecholamine metabolites before and after adrenalectomy in patients with pheochromocytoma.
| Variables | Before ADX | After ADX | p |
|---|---|---|---|
| Catecholamine metabolites | |||
| Plasma metanephrine (nmol/L), median (IQR) | 0.44 (0.18–2.26) | 0.10 (0.08–0.13) | <0.001 |
| Plasma normetanephrine (nmol/L), median (IQR) | 3.64 (1.56–9.46) | 0.50 (0.37–0.63) | <0.001 |
| Urine metanephrine (μg/day), median (IQR) | 355.5 (110.5–1456.2) | 45.5 (29.5–70.8) | <0.001 |
| Urine normetanephrine (μg/day), median (IQR) | 1180.4 (564.2–2673.6) | 178.7 (128.2–232.0) | <0.001 |
| VFA (cm2) | 85.3 ± 57.4 | 97.7 ± 59.4 | <0.001 |
| SFA (cm2) | 125.5 ± 67.1 | 145.3 ± 65.9 | <0.001 |
| SMA (cm2) | 129.0 ± 31.6 | 129.4 ± 31.5 | 0.531 |
| SMI (cm2/m2) | 48.6 ± 9.1 | 48.6 ± 8.9 | 0.746 |
All p-values were calculated using the paired t-test or Wilcoxon signed-rank test, as appropriate. Bold means that values are statistically significant. ADX, adrenalectomy; IQR, interquartile range; VFA, visceral fat area; SFA, subcutaneous fat area; SMA, skeletal muscle area; SMI, skeletal muscle index.
Table 3.
Association of baseline catecholamine metabolites with changes in computed tomography-determined body composition before and after adrenalectomy in patients with pheochromocytoma.
Table 3.
Association of baseline catecholamine metabolites with changes in computed tomography-determined body composition before and after adrenalectomy in patients with pheochromocytoma.
| Independent Variable: Plasma Metanephrine | ||||||
|---|---|---|---|---|---|---|
| Change (Baseline to Follow-Up) | Unadjusted | Age and Sex-Adjusted | Multivariable-Adjusted | |||
| β (95% CI) | p | β (95% CI) | p | β (95% CIs | p | |
| ΔVFA (cm2) | 0.699 (−0.364 to 1.761) | 0.196 | 0.714 (−0.351 to 1.780) | 0.188 | 0.641 (−0.414 to 1.697) | 0.232 |
| ΔSFA (cm2) | 1.339 (0.121 to 2.558) | 0.031 | 1.471 (0.217 to 2.726) | 0.022 | 1.364 (0.134 to 2.594) | 0.030 |
| ΔSMA (cm2) | −0.070 (−0.398 to 0.259) | 0.677 | −0.057 (−0.395 to −0.281) | 0.738 | −0.084 (−0.418 to 0.250) | 0.619 |
| ΔSMI (cm2/m2) | −0.014 (−0.133 to 0.105) | 0.822 | −0.015 (−0.137 to 0.108) | 0.813 | −0.023 (−0.145 to 0.100) | 0.716 |
| Independent Variable: Plasma Normetanephrine | ||||||
| Change (Baseline to Follow-Up) | Unadjusted | Age and Sex-Adjusted | Multivariable-Adjusted | |||
| β (95% CI) | p | β (95% CI) | p | β (95% CI) | p | |
| ΔVFA (cm2) | 0.278 (−0.124 to 0.680) | 0.175 | 0.307 (−0.087 to 0.701) | 0.126 | 0.266 (−0.124 to 0.656) | 0.180 |
| ΔSFA (cm2) | 0.406 (−0.057 to 0.870) | 0.085 | 0.407 (−0.060 to 0.875) | 0.087 | 0.347 (−0.111 to 0.805) | 0.137 |
| ΔSMA (cm2) | 0.114 (−0.009 to 0.237) | 0.069 | 0.116 (−0.008 to 0.240) | 0.067 | 0.103 (−0.020 to 0.225) | 0.100 |
| ΔSMI (cm2/m2) | 0.047 (0.002 to 0.091) | 0.040 | 0.048 (0.003 to 0.093) | 0.036 | 0.044 (−0.001 to 0.089) | 0.052 |
| Independent Variable: Urine Metanephrine | ||||||
| Change (Baseline to Follow-Up) | Unadjusted | Age and Sex-Adjusted | Multivariable-Adjusted | |||
| β (95% CI) | p | β (95% CI) | p | β (95% CI) | p | |
| ΔVFA (cm2) | 0.046 (−0.092 to 0.184) | 0.516 | 0.041 (−0.095 to 0.176) | 0.556 | 0.041 (−0.092 to 0.175) | 0.543 |
| ΔSFA (cm2) | 0.084 (−0.070 to 0.237) | 0.282 | 0.087 (−0.069 to 0.242) | 0.274 | 0.083 (−0.070 to 0.236) | 0.284 |
| ΔSMA (cm2) | −0.021 (−0.065 to 0.023) | 0.355 | −0.019 (−0.063 to 0.025) | 0.401 | −0.021 (−0.064 to 0.022) | 0.328 |
| ΔSMI (cm2/m2) | −0.006 (−0.022 to 0.010) | 0.463 | −0.006 (−0.022 to 0.010) | 0.494 | −0.007 (−0.022 to 0.009) | 0.414 |
| Independent Variable: Urine Normetanephrine | ||||||
| Change (Baseline to Follow-Up) | Unadjusted | Age and Sex-Adjusted | Multivariable-Adjusted | |||
| β (95% CI) | p | β (95% CI) | p | β (95% CI) | p | |
| ΔVFA (cm2) | 0.148 (−0.001 to 0.297) | 0.052 | 0.143 (−0.006 to 0.292) | 0.059 | 0.122 (−0.026 to 0.271) | 0.106 |
| ΔSFA (cm2) | 0.290 (0.128 to 0.453) | 0.001 | 0.300 (0.132 to 0.467) | 0.001 | 0.291 (0.125 to 0.458) | 0.001 |
| ΔSMA (cm2) | 0.047 (−0.001 to 0.095) | 0.053 | 0.040 (−0.009 to 0.088) | 0.106 | 0.041 (−0.007 to 0.089) | 0.091 |
| ΔSMI (cm2/m2) | 0.019 (0.001 to 0.036) | 0.035 | 0.017 (−0.001 to 0.034) | 0.063 | 0.017 (0 to 0.035) | 0.050 |
All p-values were calculated using multivariable linear regression analyses. The multivariable adjustment model includes age, sex, body mass index, and follow-up duration. Bold indicates values are statistically significant. CI, confidence interval; VFA, visceral fat area; SFA, subcutaneous fat area; SMA, skeletal muscle area; SMI, skeletal muscle index.
Table 4.
Association between changes in catecholamine metabolites and changes in computed tomography-determined body composition before and after adrenalectomy in patients with pheochromocytoma.
Table 4.
Association between changes in catecholamine metabolites and changes in computed tomography-determined body composition before and after adrenalectomy in patients with pheochromocytoma.
| Independent Variable: ΔPlasma Metanephrine (Baseline to Follow-Up) | ||||||
|---|---|---|---|---|---|---|
| Change (Baseline to Follow-Up) | Unadjusted | Age and Sex-Adjusted | Multivariable-Adjusted | |||
| β (95% CI) | p | β (95% CI) | p | β (95% CI) | p | |
| ΔVFA (cm2) | −0.740 (−1.832 to 0.353) | 0.183 | −0.766 (−1.871 to 0.340) | 0.173 | −0.658 (−1.755 to 0.440) | 0.238 |
| ΔSFA (cm2) | −1.352 (−2.614 to −0.090) | 0.036 | −1.498 (−2.805 to −0.190) | 0.025 | −1.343 (−2.626 to −0.060) | 0.040 |
| ΔSMA (cm2) | 0.072 (−0.265 to 0.409) | 0.675 | 0.062 (−0.287 to 0.411) | 0.726 | 0.098 (−0.247 to 0.443) | 0.575 |
| ΔSMI (cm2/m2) | 0.017 (−0.105 to 0.139) | 0.788 | 0.019 (−0.107 to 0.146) | 0.763 | 0.030 (−0.095 to 0.156) | 0.633 |
| Independent Variable: ΔPlasma Normetanephrine (Baseline to Follow-up) | ||||||
| Change (Baseline to Follow-Up) | Unadjusted | Age and Sex-Adjusted | Multivariable-Adjusted | |||
| β (95% CI) | p | β (95% CI) | p | β (95% CI) | p | |
| ΔVFA (cm2) | −0.302 (−0.716 to 0.113) | 0.152 | −0.322 (−0.729 to 0.085) | 0.120 | −0.276 (−0.680 to 0.129) | 0.180 |
| ΔSFA (cm2) | −0.433 (−0.914 to 0.048) | 0.077 | −0.431 (−0.917 to 0.054) | 0.081 | −0.361 (−0.837 to 0.115) | 0.136 |
| ΔSMA (cm2) | −0.112 (−0.238 to 0.015) | 0.084 | −0.112 (−0.240 to 0.015) | 0.084 | −0.097 (−0.224 to 0.029) | 0.131 |
| ΔSMI (cm2/m2) | −0.044 (−0.090 to 0.001) | 0.058 | −0.045 (−0.091 to 0.001) | 0.054 | −0.041 (−0.087 to 0.005) | 0.081 |
| Independent Variable: ΔUrine Metanephrine (Baseline to Follow-Up) | ||||||
| Change (Baseline to Follow-Up) | Unadjusted | Age and Sex-Adjusted | Multivariable-Adjusted | |||
| β (95% CI) | p | β (95% CI) | p | β (95% CI) | p | |
| ΔVFA (cm2) | 0.006 (−0.150 to 0.162) | 0.941 | 0.0004 (−0.154 to 0.155) | 0.995 | −0.005 (−0.157 to 0.148) | 0.953 |
| ΔSFA (cm2) | −0.026 (−0.204 to 0.152) | 0.773 | −0.027 (−0.207 to 0.153) | 0.767 | −0.031 (−0.207 to 0.145) | 0.727 |
| ΔSMA (cm2) | 0.027 (−0.024 to 0.078) | 0.296 | 0.024 (−0.026 to 0.075) | 0.347 | 0.024 (−0.025 to 0.074) | 0.337 |
| ΔSMI (cm2/m2) | 0.008 (−0.010 to 0.027) | 0.383 | 0.007 (−0.011 to 0.026) | 0.435 | 0.007 (−0.011 to 0.025) | 0.423 |
| Independent Variable: ΔUrine Normetanephrine (Baseline to Follow-Up) | ||||||
| Change (Baseline to Follow-Up) | Unadjusted | Age and Sex-Adjusted | Multivariable-Adjusted | |||
| β (95% CI) | p | β (95% CI) | p | β (95% CI) | p | |
| ΔVFA (cm2) | −0.128 (−0.287 to 0.031) | 0.113 | −0.124 (−0.285 to 0.038) | 0.132 | −0.108 (−0.270 to 0.053) | 0.187 |
| ΔSFA (cm2) | −0.311 (−0.488 to −0.134) | 0.001 | −0.327 (−0.509 to −0.145) | 0.001 | −0.319 (−0.499 to −0.139) | 0.001 |
| ΔSMA (cm2) | −0.052 (−0.104 to 0.001) | 0.053 | −0.047 (−0.100 to 0.006) | 0.080 | −0.047 (−0.100 to 0.005) | 0.075 |
| ΔSMI (cm2/m2) | −0.021 (−0.040 to −0.002) | 0.034 | −0.019 (−0.039 to −0.0002) | 0.048 | −0.020 (−0.039 to −0.001) | 0.042 |
All p-values were calculated using multivariable linear regression analyses. The multivariable adjustment model includes age, sex, body mass index, and follow-up duration. Bold indicates values are statistically significant. CI, confidence interval; VFA, visceral fat area; SFA, subcutaneous fat area; SMA, skeletal muscle area; SMI, skeletal muscle index.
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Ko, Y.; Jeong, H.; Khang, S.; Lee, J.; Kim, K.W.; Kim, B.-J. Change of Computed Tomography-Based Body Composition after Adrenalectomy in Patients with Pheochromocytoma. Cancers 2022, 14, 1967. https://doi.org/10.3390/cancers14081967
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Ko Y, Jeong H, Khang S, Lee J, Kim KW, Kim B-J. Change of Computed Tomography-Based Body Composition after Adrenalectomy in Patients with Pheochromocytoma. Cancers. 2022; 14(8):1967. https://doi.org/10.3390/cancers14081967
Chicago/Turabian StyleKo, Yousun, Heeryoel Jeong, Seungwoo Khang, Jeongjin Lee, Kyung Won Kim, and Beom-Jun Kim. 2022. "Change of Computed Tomography-Based Body Composition after Adrenalectomy in Patients with Pheochromocytoma" Cancers 14, no. 8: 1967. https://doi.org/10.3390/cancers14081967
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