Abstract
Background
Catecholamine excess in patients with pheochromocytomas or paragangliomas (PPGLs) can lead to hypertension, diabetes and hyperlipidemia. The aim was to investigate the prevalence of hyperlipidemia and the effect of surgical resection.
Methods
One hundred and thirty-two patients with PPGLs underwent an operation at the National Institutes of Health from 2009 to 2016, of which 54 patients met the inclusion criteria. Clinical demographics, BMI, genetic mutations, tumor size, perioperative catecholamine levels and perioperative lipid panels were retrospectively reviewed. Spearman correlation between catecholamines and lipid levels was evaluated. Paired Wilcoxon and paired t test were used to analyze differences in pre- and postoperative lipid levels.
Results
Preoperatively, 51 patients (94.4%) had elevated catecholamines, thirteen (24.1%) had elevated total cholesterol (TC) (>200 mg/dL), nine (16.6%) had elevated LDL (>130 mg/dL) and ten (18.5%) had elevated triglycerides (>150 mg/dL). Serum and urinary metanephrine levels were positively associated with TC (r = 0.2792, p = 0.0372 and r = 0.4146, p = 0.0031, respectively) and LDL levels (r = 0.2977, p = 0.0259 and r = 0.4434, p = 0.0014, respectively). Mean TC decreased from 176.4 to 166.3 mg/dL (p = 0.0064) and mean HDL decreased from 56.7 to 53.2 mg/dL (p = 0.0253) after PPGL resection (median 3.1 months (range 1.3–50.2) between lipid panels). Most patients with elevated TC (76.9%) had improvement with mean TC decreasing from 225 to 200.2 mg/dL (p = 0.0230). Of patients with elevated LDL, 66.7% had improvement with mean LDL decreasing from 149 to 131.1 mg/dL (p = 0.0313).
Conclusions
The prevalence of hyperlipidemia in patients with PPGLs is 46%. Future prospective studies are needed to determine whether surgical resection improves TC and/or LDL levels.
Introduction
Pheochromocytomas and paragangliomas (PPGLs), rare neuroendocrine tumors, arise from chromaffin cells in the adrenal medulla or extra-adrenal sympathetic or parasym-pathetic ganglia. The annual incidence is 2–8 per million with an equal distribution between males and females [1] and up to 41% of PPGLs may be associated with germline genetic mutations [2–5]. PPGLs produce, store, metabolize and secrete catecholamines and/or their metabolites [6], which are responsible for many hemodynamic and metabolic physiological changes [7]. The classic triad of symptoms includes headache, palpitations and diaphoresis in the setting of hypertension, but can be variable. In addition to causing hypertension, PPGLs have deleterious effects on multiple organ systems.
The uncontrolled release of catecholamines in patients with PPGLs has been linked to vascular remodeling [8], stress-induced cardiomyopathy [1, 9], diabetes [10], hypertension [11] and hyperlipidemia [12, 13], all of which increase the risk of cardiovascular disease (CVD), morbidity and mortality [14]. While vascular remodeling has not been clearly shown to improve after surgical resection [8], cardiomyopathy [9] and diabetes [10] have shown improvement in 96% and 93% of patients, respectively. In patients with PPGLs and hypertension, 36% became normotensive following resection, with the remaining experiencing a significant decrease in mean systolic blood pressure (164–143 mmHg) [11]. Few data are available in humans regarding the effects of catecholamines on lipid levels and the effect of surgical resection of PPGLs on lipid levels.
The prevalence of hyperlipidemia in patients with PPGLs has been shown to be up to 5.8-fold higher than that of healthy subjects and 2.9-fold higher than in patients with essential hypertension [15]. Although hyperlipidemia has been associated with catecholamine excess [13, 15, 16], the pathophysiology of abnormal lipid levels has not been assessed extensively in patients with PPGLs. Hyperlipidemia in patients with PPGLs may be related to increased insulin resistance induced by excess catecholamines. Insulin exerts a lipolytic effect on adipose tissue [12], which may be responsible for elevated LDL and triglyceride levels in patients with impaired glucose tolerance. The association between insulin resistance and hyperlipidemia, coupled with the previously demonstrated improvement of diabetes with surgical resection of PPGLs, suggests that hyperlipidemia in patients with PPGLs may be improved postoperatively.
PPGLs are rare tumors with multiple comorbidities that may be improved with surgical resection. While hyperlipidemia has been found to be more common in patients with PPGLs, it is unknown whether surgical resection improves hyperlipidemia. The aim was to assess the prevalence of hyperlipidemia in patients with PPGLs who underwent surgery, assess for an association between catecholamine and lipid levels, and determine the effects of surgical resection on lipid levels.
Materials and methods
Patient demographics, body mass index (BMI), genetic tests, pathology, tumor characteristics, and presence or absence of symptoms were prospectively collected among patients who underwent surgery for PPGLs at the National Institutes of Health from 2009 to 2016 under an Institutional Review Board-approved protocol (NCT01005654). Patients underwent genetic testing for mutations and deletions in SDHA, SDHB, SDHC, SDHD, SDHAF2, RET, VHL, MAX and TMEM127. Some of these tests were performed in collaboration with the Mayo Clinic in Rochester, Minnesota. Preoperative and postoperative evaluation consisted of biochemical testing (plasma and urine catecholamines, metanephrines, normetanephrines) and imaging studies (CT, MRI and 18F-FDG-PET/CT imaging). Histological evidence of PPGLs was confirmed according to the WHO classification. Inclusion criteria included patients who underwent surgical resection for PPGLs, had negative margins on final pathology (R0 resection), and had pre- and postoperative lipid panels drawn. Exclusion criteria included patients with microscopic or gross positive margins (R1 or R2 resection), with no biochemical response after resection, or without a pathologic diagnosis of PPGL. Of the total 132 patients who underwent surgery for PPGLs, 54 patients who underwent a total of 59 operative procedures had adequate pre- and postoperative follow-up data and were included in the study.
Classification of laboratory values
Biochemical laboratory values were used for the diagnosis of PPGLs. Any biochemical evidence of hormone elevation above the upper limit of normal was considered evidence of disease. The biochemical values used for the diagnosis of PPGLs included plasma fractionated metanephrines (61 pg/ml), plasma fractionated normetanephrines (112 pg/ml), serum epinephrine (83 pg/ml), serum norepinephrine (498 pg/ml), serum dopamine (46 pg/ml) and 24-h urinary fractionated metanephrine and normetanephrine (400 lg/24 h). Patients were instructed to discontinue the use of medications, such as antihypertensives, that may result in false-positive results before laboratory testing, with blood pressure monitoring when off medications. Laboratory studies were performed within 3 months of surgery. Postoperative values were collected, and the duration of follow-up was recorded. Only patients with pre- and postoperative laboratory values using the same assay and drawn within 51 months of surgery were included.
Classification of lipid levels
Preoperative and postoperative lipid levels and lipid-lowering medication (statins, bile acid sequestrants, selective cholesterol absorption inhibitors, proprotein convertase subtilisin/kexin type 9 inhibitors, omega-3 fatty acids, fibrates and niacin) [17, 18] use were collected. Hyperlipidemia was defined as total cholesterol (TC) > 200 mg/dL, LDL > 130 mg/dL, triglycerides > 150 mg/dL and HDL < 40 mg/dL according to the National Heart, Lung, and Blood Institute [19].
Statistical analysis
Categorical and continuous variables were compared using a Chi-square and an independent t test, respectively. Results were reported as mean and standard deviation. Differences in pre- and postoperative lipid levels were analyzed using paired Wilcoxon and paired t tests. Spearman correlation was used to assess for an association between preoperative biochemical laboratory values, lipid levels and BMI. Variables with a p value < 0.1 on univariable analysis were included in multivariable binary logistic regression analysis. Statistical analyses were performed using SPSS version 25 (IBM, Armonk, NY) and GraphPad Prism version 7.01 (GraphPad software Inc, La Jolla, CA). For all analyses, a p value of <0.05 was considered statistically significant.
Results
Patient characteristics
Fifty-four patients who underwent 59 operations for PPGLs between 2009 and 2016 met the study inclusion criteria. Clinical and demographic characteristics of the study cohort were based on initial operation of 54 patients and are summarized in Table 1. The mean age for all patients was 41.9 years (range 11.2–74.5 years). Median follow-up time was 25.9 months (range 1.1–138.5 months). Overall survival was 96.3% (n = 52) at the last follow-up. Most patients (94.4%, n = 51) had elevated preoperative catecholamine levels (Table 2). All patients with elevated catecholamines had a biochemical response and normalization of their catecholamine levels following surgical resection.
Table 1.
Comparison of PPGL patients with and without abnormal lipid levels
| All patients (n = 54) | Normal lipids (n = 29) | Abnormal lipids (n = 25) | p value | |
|---|---|---|---|---|
| Sex [n (%)] | 0.034 | |||
| Male | 22 (40.7) | 8 (25.6) | 14 (56.0) | |
| Female | 32 (59.3) | 21 (72.4) | 11 (44.0) | |
| Age at surgery (years), [mean ± SD] | 41.9 ± 16.2 | 36.2 ± 16.8 | 47.3 ± 13.4 | 0.010 |
| Body mass index (kg/m2), [mean ± SD] | 27.4 ± 7.0 | 25.9 ± 6.8 | 29.1 ± 7.0 | 0.093 |
| Symptoms at diagnosis [n (%)] | 0.356 | |||
| Asymptomatic | 14 (25.9) | 9 (31.0) | 5 (20.0) | |
| Symptomatic | 40 (74.1) | 20 (69.0) | 20 (80.0) | |
| Persistent hypertension | 28 (51.9) | |||
| Headache | 24 (44.4) | |||
| Palpitations | 26 (48.1) | |||
| Diaphoresis | 21 (38.9) | |||
| Primary tumor location | 0.198 | |||
| Adrenal pheochromocytoma [n (%)] | 41 (75.9) | 20 (69.0) | 21 (84.0) | |
| Unilateral (n) | 34 | |||
| Bilateral (n) | 7 | |||
| Extra-adrenal (paraganglioma) [n (%)] | 13 (24.1) | 9 (31.0) | 4 (16.0) | |
| Periaortic paraganglioma (n) | 10 | |||
| Bladder paraganglioma (n) | 3 | |||
| Tumor size (cm) | 4.3 ± 2.3 | 3.9 ± 1.6 | 4.8 ± 2.8 | 0.154 |
| Abnormal lipids [n (%)] | 25 (46.3) | N/A | 25 (100) | |
| Elevated cholesterol | 13 (24.1) | N/A | 13 (52) | |
| Elevated LDL | 9 (16.6) | N/A | 9 (36) | |
| Elevated Triglycerides | 10 (18.5) | N/A | 10 (40) | |
| Decreased HDL | 9 (16.6) | N/A | 9 (36) | |
| Genetic testing resultsa [n (%)] | 0.579 | |||
| 21-hydroxylase deficiency | 1 (1.9) | 1 (3.4) | 0 | |
| FHb | 2 (3.7) | 1 (3.4) | 1 (4.0) | |
| HIF2A | 3 (5.5) | 2 (6.9) | 1 (4.0) | |
| KIF1Bb | 1 (1.9) | 0 | 1 (4.0) | |
| MAX | 1 (1.9) | 1 (3.4) | 0 | |
| MEN2A | 4 (7.4) | 3 (10.3) | 1 (4.0) | |
| MEN2B | 1 (1.9) | 1 (3.4) | 0 | |
| NF1 | 1 (1.9) | 1 (3.4) | 0 | |
| PDH2 | 1 (1.9) | 1 (3.4) | 0 | |
| SDHB | 10 (18.5) | 5 (17.2) | 5 (20.0) | |
| VHL | 2 (3.7) | 1 (3.4) | 1 (4.0) | |
| Sporadic without known mutation | 28 (51.9) | 12 (41.4) | 16 (64.0) | |
| Lipid-lowering medications [n (%)] | 0.725 | |||
| Preoperative | 6 (11.1) | 4 (13.7) | 2 (8.0) | |
| Postoperative | 7 (13.0) | 4 (13.7) | 3 (12.0) |
p values < 0.05 were considered statistically significant and are listed in bold
FH fumarase hydratase mutation; HIF2A Hypoxia-inducible factor 2α mutation; KIF1B kinesin family member 1B mutation; MAX mycassociated factor X mutation; MEN2A multiple endocrine neoplasia type 2A; MEN2B multiple endocrine neoplasia type 2B; NF1 neurofibromatosis 1; PDH2 prolyl hydroxylase domain 2 mutation; SDHB succinate dehydrogenase complex subunit B mutation; VHL Von Hippel–Lindau
One patient had FH and KIF1B germline mutations
Table 2.
Preoperative biochemical data for all patients (n = 54)
| Laboratory test | na | Number with elevated levels, n (%) | Mean ± SD |
|---|---|---|---|
| Elevated biochemical levels [n (%)] | 54 | 51 (94.4) | |
| Dopamine, serum (ULN = 29 pg/mL) | 50 | 16 (32) | 71 ± 242 |
| Epinephrine, serum (ULN = 50 pg/mL) | 50 | 17 (34) | 98 ± 186 |
| Norepinephrine, serum (ULN = 750 pg/mL) | 50 | 30 (60) | 2631 ± 3396 |
| Fractionated metanephrines, serum (ULN = 61 pg/mL) | 52 | 25 (48.1) | 307 ± 769 |
| Fractionated normetanephrines, serum (ULN =112 pg/mL) | 53 | 48 (90.6) | 1183 ± 1547 |
| Fractionated metanephrines, urine (ULN =185 mcg/24 h) | 46 | 26 (56.5) | 2415 ± 5208 |
Number of patients with the available data
ULN upper limit of normal, SD standard deviation
Prevalence of hyperlipidemia
Forty-six percent (n = 25) of patients had abnormal preoperative lipids: 13 (24.1%) had elevated TC, 9 (16.6%) had elevated LDL, 10 (18.5%) had elevated triglycerides and 9 (16.6%) had low HDL. Six patients were on lipid-lowering medications preoperatively, which were continued throughout the duration of the study (Table 1). One patient was started on omega-3 fatty acids postoperatively. Otherwise, no new lipid-lowering medications were initiated. Clinical features associated with preoperative hyperlipidemia included male sex and older age (p = 0.034 and 0.010, respectively) on univariable analysis (Table 1). There was no association between patients with PPGLs and hyperlipidemia and preoperative symptoms, BMI, tumor location, tumor size, germline mutation or lipid-lowering medication usage. On multivariable analysis, no variables were significantly associated with preoperative lipid levels.
Association of lipid levels with catecholamine excess and BMI
Elevated serum and 24-h urinary metanephrine levels were positively associated with TC (r = 0.2792, p = 0.0372 and r = 0.4146, p = 0.0031, respectively) and LDL levels (r = 0.2977, p = 0.0259 and r = 0.4434, p = 0.0014, respectively) on a Spearman correlation analysis, which included data for all 59 operations (Fig. 1a–d). There was no association between dopamine, epinephrine, norepinephrine, or normetanephrines and lipid levels. BMI was positively associated with LDL (r = 0.2668, p = 0.0469) and triglyceride levels (r = 0.3527, p = 0.0077), and negatively associated with HDL levels (r = −0.4136, p = 0.0015) (Fig. 1e–g).
Fig. 1.
Association of lipid levels with catecholamine excess and body mass index (BMI). Serum metanephrine (a) and urine fractionated metanephrine (b) showed a significant positive association with total cholesterol level. Serum metanephrine (c) and urine fractionated metanephrine (d) showed a significant positive association with LDL level. BMI showed a significant positive association with LDL (e) and triglyceride (f) levels and negative association with HDL level (g). BMI body mass index, HDL high-density lipoprotein, LDL low-density lipoprotein
Effect of PPGL resection on lipid levels
Pre- and postoperative lipid levels were evaluated for the effect of PPGL resection (Table 3). The median time between lipid panels was 3.1 months (range 1.3–50.2). For all patients, mean TC decreased from 176.4 to 166.3 mg/dL (p = 0.0064) and mean HDL decreased from 56.7 to 53.2 mg/dL (p = 0.0253) after surgical resection of PPGLs (Fig. 2a, b). Of patients with elevated preoperative TC, 10/13 (76.9%) had improvement and 6/13 (46.2%) patients had postoperative normalization of TC. In this group, mean TC decreased from 225 to 200.2 mg/dL (p = 0.0230) and mean HDL decreased from 60.2 to 51.5 mg/dL (p = 0.0111) (Fig. 2c, d). Of patients with elevated preoperative LDL, 6/9 (66.7%) had improvement and 3/9 (33.3%) patients had postoperative normalization of LDL. The mean LDL decreased from 149.0 to 131.1 mg/dL (p = 0.0313). Additionally, patients with elevated preoperative LDL had a decrease in mean TC from 228.1 to 200.2 mg/dL (p = 0.0234) (Fig. 2e, f). Of patients with low preoperative HDL, 5/9 (55.6%) had improvement and mean HDL increased from 33.2 to 37.8 mg/dL, although this value did not reach statistical significance (p = 0.3281). There was no significant change in lipid levels in patients with elevated preoperative triglycerides following surgical resection of PPGLs.
Table 3.
Changes in lipid levels after resection of PPGL
| Preoperative value (mg/dL, mean ± SD) | Postoperative value (mg/dL, mean ± SD) | p value | |
|---|---|---|---|
| Total patients (n = 54) | |||
| Total cholesterol | 176.4 ± 34.78 | 166.3 ± 35.53 | 0.0064 |
| LDL | 97.0 ± 31.5 | 92.3 ± 33.0 | 0.1767 |
| Triglycerides | 117.2 ± 67.8 | 113.2 ± 84.2 | 0.1701 |
| HDL | 56.7 ± 16.6 | 53.2 ± 14.7 | 0.0253 |
| Elevated total cholesterol (n = 13) | |||
| Total cholesterol | 225.0 ± 20.1 | 200.2 ± 35.1 | 0.0230 |
| LDL | 139.2 ± 20.2 | 128.8 ± 28.5 | 0.2324 |
| Triglycerides | 137.6 ± 80.4 | 153.6 ± 152.5 | 0.8926 |
| HDL | 60.2 ± 15.4 | 51.5 ± 17.1 | 0.0111 |
| Elevated LDL (n = 9) | |||
| Total cholesterol | 228.1 ± 22.9 | 200.2 ± 37 | 0.0234 |
| LDL | 149.0 ± 18.6 | 131.1 ± 33.2 | 0.0313 |
| Triglycerides | 143.0 ± 94.8 | 186.0 ± 175.0 | 0.5703 |
| HDL | 53.4 ± 11.8 | 47.9 ± 16.1 | 0.2578 |
| Elevated triglycerides (n= 10) | |||
| Total cholesterol | 197.5 ± 44.4 | 176.9 ± 43.8 | 0.1022 |
| LDL | 109.1 ± 47.7 | 103.3 ± 42.3 | 0.9320 |
| Triglycerides | 240.0 ± 69.2 | 230.5 ± 143.2 | 0.8170 |
| HDL | 43.2 ± 7.1 | 39.1 ± 6.4 | 0.1079 |
| Decreased HDL (n = 9) | |||
| Total cholesterol | 168.2 ± 43.8 | 149.4 ± 26.0 | 0.1602 |
| LDL | 99.0 ± 37.1 | 84.4 ± 27.1 | 0.2734 |
| Triglycerides | 180.1 ± 101.7 | 175.4 ± 152.4 | 0.3750 |
| HDL | 33.2 ± 7.9 | 37.8 ± 7.0 | 0.3281 |
p values < 0.05 were considered statistically significant and are listed in bold
Fig. 2.
Changes in lipid levels before and after surgical resection of PPGLs. Change in total cholesterol (a) and HDL (b) levels in all patients who underwent surgical resection of PPGLs. Change in total cholesterol (c) and HDL (d) levels in patients with elevated preoperative total cholesterol. Change in total cholesterol (e) and LDL (f) levels in patients with elevated preoperative LDL. HDL high-density lipoprotein, LDL low-density lipoprotein
Discussion
PPGLs induce numerous physiological changes, resulting in vascular remodeling, stress-induced cardiomyopathy, hypertension, diabetes and hyperlipidemia. In this study, the prevalence of hyperlipidemia was found to be 46% for patients with PPGLs undergoing surgical resection who underwent perioperative lipid panels. As hypothesized, there was a positive association between metanephrine levels and multiple biomarkers of hyperlipidemia including TC and LDL. For the first time, surgical resection of PPGLs was associated with improved TC. In addition, for patients with hyperlipidemia, surgical resection of PPGLs improved the TC and LDL levels.
Hyperlipidemia is a major risk factor for CVD including heart attack and stroke due to the role of lipids in the development of atherosclerosis [20]. The prevalence of hyperlipidemia in patients with PPGLs ranges from 31 to 65%. In this study, hyperlipidemia was present in 46% of patients, which was consistent with previous reports. Furthermore, older age and male sex were positively associated with hyperlipidemia in patients with PPGLs. As age is a known independent risk factor for hyperlipidemia [19], this finding was not surprising. Previous data on sex distributions are more variable. Although women in the USA have a higher prevalence overall [21], the distribution of hyperlipidemia is predominately male among hypertensive patients [22]. These findings are likely multifactorial, in part related to sex differences in terms of healthcare-seeking behavior and access to healthcare [23]. Further studies are required to assess the sex distribution and whether female sex may have an added protective effect against hyperlipidemia in the setting of PPGLs.
Although partially attributed to increased circulating catecholamines, the pathophysiology of hyperlipidemia in patients with PPGLs has not been fully elucidated. Impaired glucose tolerance, which can occur in up to 35% of patients with PPGLs [24], leads to elevated LDL and triglyceride levels and reduced HDL levels [20]. Resection of PPGLs has been shown to improve diabetes in these patients. Therefore, catecholamine excess may be responsible for decreased inhibition of lipolysis by insulin, thereby exerting a lipolytic effect on adipose tissue [12]. Furthermore, decreased activity of lecithin–cholesterol acyltransferase, an enzyme which breaks down free cholesterol, has been demonstrated in patients with pheochromocytoma compared to both healthy subjects and patients with essential hypertension. This finding suggests that catecholamines play a role in the etiology of hyperlipidemia in patients with PPGLs by leading to either increased synthesis or decreased catabolism of lipoproteins [15].
Associations between increased catecholamines and elevated TC and LDL have been previously demonstrated in patients with pheochromocytoma, but no significant link between biochemical markers and TC, LDL or triglyceride levels has been made [13, 15]. The lack of statistical significance in previous reports could be attributed to small sample size. In this cohort of 54 patients with PPGLs, serum and urinary fractionated metanephrine levels were positively associated with TC and LDL levels, supporting a pathophysiological role, and perhaps a dose–response relationship, between catecholamine excess and hyperlipidemia. This evidence endorses that all patients with PPGLs should have a screening lipid panel and be treated appropriately.
Since elevated catecholamines are associated with hyperlipidemia, resection of PPGLs was hypothesized to lead to improvement in lipid levels. Okumara and colleagues demonstrated a decrease in mean LDL levels (from 115 ± 28 to 105 ± 22 mg/dL, p = 0.14) following a surgical resection in 42 patients with PPGLs [13]. In this study, a significant decrease in mean TC and HDL levels following surgical resection of PPGLs was found for all patients. Hyperlipidemia, a known risk factor for CVD disease, could potentially increase the long-term cardiac morbidity and mortality for these patients [14]. Surgical resection of PPGLs has been reported to improve cardiac function through amelioration of catecholamine-induced cardiomyopathy [9]. Postoperative improvement in hyperlipidemia could further decrease the risk of CVD, a well- established morbidity in patients with PPGLs [25]. For patients with hyperlipidemia, TC, LDL, and HDL levels also decreased after surgical resection of PPGLs, which is compatible with previous findings [13]. Patients with PPGLs and elevated TC and LDL may derive the greatest benefit, since the majority of these patients had improvement with one-third to one half becoming normolipidemic postoperatively. Although HDL is considered “good” cholesterol, the benefits of a higher HDL may not outweigh the deleterious effects of PPGLs and hyperlipidemia. Additionally, an increase in mean HDL levels was observed in the subgroup of patients with low preoperative HDL, albeit not statistically significant.
There are several limitations since this was a single-institution experience with a limited sample size and therefore subject to inherent selection and referral bias. However, this is a large cohort for a rare disease. Given the retrospective nature of this study, biochemical levels were not systematically obtained. However, all patients had a biochemical response, and therefore, the association of surgical resection and hyperlipidemia could be assessed accurately. Regardless, a multicenter prospective study is required to validate these findings. Additionally, the prevalence of hyperlipidemia in patients with PPGLs may be falsely elevated due to selection bias introduced by the clinical decision to measure lipids. Timing between surgical resection and lipid levels was not prospectively defined and was based on patient ability to travel for follow-up. Factors such as diet and exercise may have influenced hyperlipidemia in patients with long-interval follow-up. The fasting status of patients prior to lipid panels was not available. However, TC and HDL levels have been shown to be no different in predicting cardiovascular risk in patients with fasting vs non-fasting laboratories [20]. Additionally, confounding factors such as obesity, lipid-lowering medications and genetic predisposition may influence lipid levels. Although not associated with the prevalence of hyperlipidemia, BMI was shown to negatively associate with HDL and positively associate with LDL and triglyceride levels, which may be attributed to the sample size. Lipid-lowering medications were identified in six patients preoperatively and one additional patient postoperatively. Four patients on lipid-lowering medications had normal preoperative lipid levels, perhaps masking an even higher prevalence of hyperlipidemia in patients with PPGLs. However, these patients did not comprise a large portion of the cohort. Finally, familial hyperlipidemia was not assessed.
Conclusions
Given the high prevalence of hyperlipidemia and improvement in lipid profile postoperatively, patients with PPGLs should be screened for hyperlipidemia and counseled regarding the potential benefit of surgical resection. Further analysis in the form of a systematic prospective study is needed to evaluate these results and the possible clinical significance of hyperlipidemia in patients with PPGLs with respect to long-term cardiac morbidity and mortality.
Funding
This research was supported by the Intramural Research Program of NIH.
Footnotes
This paper was presented as an oral presentation at the IAES meeting/48th World Congress of Surgery August 11–15, 2019 in Kraków, Poland.
Conflict of interest
The authors declare that they have no conflicts of interest.
References
- 1.Kiernan CM, Solorzano CC (2016) Pheochromocytoma and paraganglioma: diagnosis, genetics, and treatment. Surg Oncol Clin N Am 25(1):119–138. 10.1016/j.soc.2015.08.006 [DOI] [PubMed] [Google Scholar]
- 2.Benn DE, Robinson BG (2006) Genetic basis of phaeochromocytoma and paraganglioma. Best Pract Res Clin Endocrinol Metab 20(3):435–450. 10.1016/j.beem.2006.07.005 [DOI] [PubMed] [Google Scholar]
- 3.Fishbein L, Merrill S, Fraker DL, Cohen DL, Nathanson KL (2013) Inherited mutations in pheochromocytoma and paraganglioma: why all patients should be offered genetic testing. Ann Surg Oncol 20(5):1444–1450. 10.1245/s10434-013-2942-5 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Gimenez-Roqueplo AP et al. (2003) Mutations in the SDHB gene are associated with extra-adrenal and/or malignant phaeochromocytomas. Cancer Res 63(17):5615–5621 [PubMed] [Google Scholar]
- 5.Pacak K (2007) Preoperative management of the pheochromocytoma patient. J Clin Endocrinol Metab 92(11):4069–4079. 10.1210/jc.2007-1720 [DOI] [PubMed] [Google Scholar]
- 6.Chen H et al. (2010) The North American Neuroendocrine Tumor Society consensus guideline for the diagnosis and management of neuroendocrine tumors: pheochromocytoma, paraganglioma, and medullary thyroid cancer. Pancreas 39(6):775–783. 10.1097/MPA.0b013e3181ebb4f0 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Manger WM (2006) An overview of pheochromocytoma: history, current concepts, vagaries, and diagnostic challenges. Ann N Y Acad Sci 1073:1–20. 10.1196/annals.1353.001 [DOI] [PubMed] [Google Scholar]
- 8.Bernini G et al. (2006) Carotid vascular remodeling in patients with pheochromocytoma. J Clin Endocrinol Metab 91(5):1754–1760. 10.1210/jc.2005-2199 [DOI] [PubMed] [Google Scholar]
- 9.Zhang R, Gupta D, Albert SG (2017) Pheochromocytoma as a reversible cause of cardiomyopathy: analysis and review of the literature. Int J Cardiol 249:319–323. 10.1016/j.ijcard.2017.07.014 [DOI] [PubMed] [Google Scholar]
- 10.Beninato T et al. (2017) Resection of pheochromocytoma improves diabetes mellitus in the majority of patients. Ann Surg Oncol 24(5):1208–1213. 10.1245/s10434-016-5701-6 [DOI] [PubMed] [Google Scholar]
- 11.Timmers HJ et al. (2008) Metastases but not cardiovascular mortality reduces life expectancy following surgical resection of apparently benign pheochromocytoma. Endocr Relat Cancer 15(4):1127–1133. 10.1677/ERC-08-0049 [DOI] [PubMed] [Google Scholar]
- 12.Colwell JA (1969) Inhibition of insulin secretion by catecholamines in pheochromocytoma. Ann Intern Med 71(2):251–256 [DOI] [PubMed] [Google Scholar]
- 13.Okamura T et al. (2015) Changes in visceral and subcutaneous fat mass in patients with pheochromocytoma. Metabolism 64(6):706–712. 10.1016/j.metabol.2015.03.004 [DOI] [PubMed] [Google Scholar]
- 14.Khorram-Manesh A et al. (2005) Long-term outcome of a large series of patients surgically treated for pheochromocytoma. J Intern Med 258(1):55–66. 10.1111/j.1365-2796.2005.01504.x [DOI] [PubMed] [Google Scholar]
- 15.Berent H et al. (1987) Lipids and beta-thromboglobulin in patients with pheochromocytoma. J Clin Hypertens 3(4):389–396 [PubMed] [Google Scholar]
- 16.Maduka IC, Neboh EE, Ufelle SA (2015) The relationship between serum cortisol, adrenaline, blood glucose and lipid profile of undergraduate students under examination stress. Afr Health Sci 15(1):131–136. 10.4314/ahs.v15i1.18 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.American Heart Association, Cholesterol medications, https://www.heart.org/en/health-topics/cholesterol/prevention-and-treatment-of-high-cholesterol-hyperlipidemia/cholesterol-medications. 10 November 2018
- 18.Chaudhary R, Garg J, Shah N, Sumner A (2017) PCSK9 inhibitors: a new era of lipid lowering therapy. World J Cardiol 9(2):76–91. 10.4330/wjc.v9.i2.76 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.National Heart Lung and Blood Institute. High cholesterol what you need to know, https://www.nhlbi.nih.gov/files/docs/public/heart/wyntk.pdf. June 2005
- 20.Kopin L, Lowenstein C (2017) Dyslipidemia. Ann Intern Med. 167(11):ITC81–ITC96. 10.7326/aitc201712050 [DOI] [PubMed] [Google Scholar]
- 21.Centers for Disease Control and Prevention. Total and high-density lipoprotein cholesterol in adults: United States, 2015–2016, https://www.cdc.gov/nchs/products/databriefs/db290.htm. 26 October 2017
- 22.O’Meara JG et al. (2004) Ethnic and sex differences in the prevalence, treatment, and control of dyslipidemia among hypertensive adults in the GENOA study. Arch Intern Med 164(12):1313–1318. 10.1001/archinte.164.12.1313 [DOI] [PubMed] [Google Scholar]
- 23.Goff DC Jr et al. (2006) Dyslipidemia prevalence, treatment, and control in the Multi-Ethnic Study of Atherosclerosis (MESA): gender, ethnicity, and coronary artery calcium. Circulation 113(5):647–656. 10.1161/CIRCULATIONAHA.105.552737 [DOI] [PubMed] [Google Scholar]
- 24.La Batide-Alanore A, Chatellier G, Plouin PF (2003) Diabetes as a marker of pheochromocytoma in hypertensive patients. J Hypertens 21(9):1703–1707. 10.1097/01.hjh.0000084729.53355.ce [DOI] [PubMed] [Google Scholar]
- 25.Bai S et al. (2019) Risk factors for postoperative cardiovascular morbidity after pheochromocytoma surgery: a large single center retrospective analysis. Endocr J 66(2):165–173. 10.1507/endocrj.EJ18-0402 [DOI] [PubMed] [Google Scholar]