Serum phosphate: Does it more closely reflect the true state of acromegaly?

Journal of Clinical Neuroscience xxx (xxxx) xxx

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Clinical study

Serum phosphate: Does it more closely reflect the true state of acromegaly? Tao Xie a,1, Pei Tian a,1, Silin Wu a, Xiaobiao Zhang a,b,c,⇑, Tengfei Liu a, Ye Gu a, Chongjing Sun a, Fan Hu a a

Department of Neurosurgery, Zhongshan Hospital, Fudan University, Shanghai, China Digital Medical Research Center, Fudan University, Shanghai, China c Shanghai Key Laboratory of Medical Image Computing and Computer-Assisted Intervention, Shanghai, China b

a r t i c l e

i n f o

Article history: Received 3 May 2019 Accepted 9 November 2019 Available online xxxx Keywords: Growth hormone Pituitary adenoma Acromegaly Phosphate

a b s t r a c t An increased serum phosphate (P) level is common in acromegaly patients, however, the relationships among P, growth hormone (GH), insulin-like growth factor 1 (IGF-1) and disease status remain unknown. To reveal these relationships, we examined the association of P with comprehensive clinical data. We measured the serum P, calcium, GH, oral glucose tolerance test-GH (OGTT-GH), IGF-1, and insulin-like growth factor binding protein-3 (IGBP-3) levels in 103 acromegaly patients. SAGITÒ was used to assess the disease status comprehensively. Spearman’s rank correlation coefficient was obtained to evaluate the associations among the above parameters. Stepwise multiple linear regression analysis was performed to investigate factors independently associated factors with the SAGIT scores. The area under the receiver operating characteristic curve (AUCROC) was used to evaluate the efficacy of the percentage change in the serum phosphate level in predicting remission in patients with postoperatively discordant GH and IGF-1 levels. Hyperphosphatemia was found in 68.9% of patients at baseline. The serum P level was higher in the non-remission group, but no correlation was found between hyperphosphatemia and remission. We revealed a significant correlation between the P level and SAGITÒ score in patients both preoperatively (r = 0.659, p = 0.000) and 1-year postoperatively without remission patients (r = 0.534, p = 0.027). All biochemical levels decreased significantly postoperatively, and the GH and OGTT-GH levels achieved early stability (1 month); however, the P, IGF-1 and IGBP-3 levels showed a gradual decline. A percentage change in P of 8.12% is recommended as a cut-off value for predicting remission in patients with postoperatively discordant GH and IGF-1 levels. As a metabolic product which affected by the GH/IGF-1 axis, serum P appears to more closely reflect the comprehensive disease status in acromegaly. When the GH and IGF-1 levels are discordant during follow-up, perioperative change in the P level may be a potential predictor of remission. Ó 2019 Elsevier Ltd. All rights reserved.

1. Introduction Acromegaly is a metabolic disease characterized by a chronic excess of growth hormone (GH) and insulin-like growth factor-1 (IGF-1) [1], and it is associated with abnormal anabolic and catabolic actions [2]. The vast majority of instances of this disease are caused by a pituitary GH adenoma [3]. The adenoma secretes excess GH into the blood, while IGF-1 is primarily secreted by the liver following the binding of GH to hepatic GH receptors, which then stimulates systemic body growth and metabolic reactions [4]. ⇑ Corresponding author at: Department of Neurosurgery, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai 200032, China. E-mail address: [email protected] (X. Zhang). 1 These authors contributed equally to this work.

Theoretically, the acromegaly patients should have typical signs and symptoms. The IGF-1 level should increase in parallel with the GH concentration. However, this is not always the case [5]. Patients develop variable symptoms and associated comorbidities ranging from insidiously to obviously, and they can present with discordant GH and IGF-1 levels both before and after surgery [6]. In some clinical circumstances, evaluating the disease activity may be a challenge, and the search for further early clinical or biochemical early markers of GH hypersecretion may be helpful, especially in patients with discordant GH and IGF-1 results. Patients with acromegaly frequently have mild hyperphosphatemia that results from renal tubular P reabsorption in the proximal tubule [7,8]. The promotion of P reabsorption is mainly mediated by the effects of IGF-1 on apical membrane sodiumphosphate (Na-Pi) IIa cotransporters [9]. As previously reported,

https://doi.org/10.1016/j.jocn.2019.11.012 0967-5868/Ó 2019 Elsevier Ltd. All rights reserved.

Please cite this article as: T. Xie, P. Tian, S. Wu et al., Serum phosphate: Does it more closely reflect the true state of acromegaly?, Journal of Clinical Neuroscience, https://doi.org/10.1016/j.jocn.2019.11.012

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T. Xie et al. / Journal of Clinical Neuroscience xxx (xxxx) xxx

GH stimulates the secretion of IGF-1; which then mediates most of the P-retaining action of GH. In other words, serum P is a downstream metabolic product affected by the GH-IGF-1 axis, and this metabolite may more closely reflect the true state of the disease. SAGITÒ is a comprehensive instrument that can be used to assess the key features of acromegaly [10]: Signs and symptoms; Associated comorbidities; GH levels; IGF-1 levels; and Tumour profiles. These key features may reflect the overall clinical status of acromegaly. Thus, what kind of relationship is there between P and SAGIT, which both seem to closely reflect the status of acromegaly? When discordant GH and IGF-1 levels occurred, does the serum P level provide additional information? This study aimed to assess the associations among the serum P, GH, OGTT (oral glucose tolerance test)-GH, IGF-1, IGF-1/IGBP-3 (Insulin-like growth factor-binding protein 3) ratio and the SAGITÒ scores at baseline and postoperatively in patients with acromegaly. The relationship between the serum P level and remission rate in patients with postoperatively discordant GH and IGF-1 levels was also investigated.

2. Patients and methods Patients with a diagnosis of acromegaly who had been treated with surgery alone between October 2013 and June 2017 were retrospectively studied. The diagnosis of acromegaly was confirmed based on the criteria of newly developed guidelines [11]. Patients with preoperative renal dysfunction or thyroid dysfunction, patients treated with somatostatin analogues, and patients with postoperative hypopituitarism, were excluded from this study. In total, 103 patients were enrolled in our study. All participants provided written informed consent before taking part in the study. The study was approved by IRB of Zhongshan Hospital, Fudan University. Patients were classified into two groups according to the postoperative remission rate: the remission group (RG) and the nonremission group (NRG). All the serum samples (pre- and post-operative) were collected after an overnight fast. The assays were performed according to the manufacturer’s recommendations by skilled technical personnel. The GH, IGF-1 and IGBP3 levels were assayed by immunoradiometric assays using an autoanalyzer (Immulite 2000, Siemens). The highest measured GH value was 40 ng/ml, and no dilution was performed for values >40. The serum P level was analyzed using a standard colorimetric methods (Cobas c702, Roche). The OGTT-GH level was measured, and the GH nadir value was determined after a 75 g glucose load. The follow-up times were set as 1 month, 3 months and 12 months. The biochemical definition of disease remission was defined as a normal age-adjusted IGF-1 levels and a random GH <1 lg/l or nadirGH in OGTT <0.4 lg/l (11). GH and IGF-1 discordance was evaluated at 3 months postoperatively, and the final remission status was ascertained at 12 months postoperatively. The comprehensive disease scoring system, SAGITÒ, is multidimensional and comprises five sections that assess the key features of acromegaly: signs and symptoms (headache, sweating, joint symptoms, swelling; score S = sum of the number of symptoms, from 0 to 4); associated comorbidities (altered carbohydrate metabolism, hypertension, sleep apnea, heart disease, hypopituitarism, active malignant tumor; score A = sum of the number of comorbidities, from 0 to 6); GH levels (GH nadir by OGTT: 0.4 mg/l, score G = 0; >0.4 to <1.0 mg/l, score G = 1; 1.0 to <2.5 mg/l, score G = 2; 2.5 to <5 mg/l, score G = 3; 5 mg/l, score G = 4 or GH random: 1.0 mg/l, score G = 0; >1.0 to <2.5 mg/l, score G = 1; 2.5 to <5 mg/l, score G = 2; 5 to <10 mg/l, Score G = 3; 10 mg/l, score G = 4; score G from 0 to 4); IGF-1 levels (reported relative to age-

adjusted upper limit of normal (ULN): normal, score I = 0; <1.3 ULN, score I = 1; 1.3 to <2 ULN, score I = 2; 2 ULN, score I = 3; and score I from 0 to 3); and tumor profile (no visible tumor, score T = 0; intrasellar microtumor <10 mm, score T = 1; intrasellar macrotumor 10 mm, score T = 2; extrasellar tumor <40 mm, score T = 3; invasive tumor, score T = 4; giant tumor 40 mm, score T = 5; score T, from 0 to 5). 3. Statistical analysis All data were subjected to a normality test and homogeneity of variance test. The Normally distributed data are shown as the mean ± SD. Non-normally distributed data are shown as the median, followed by the 25% and 75% percentiles. For normally distributed data, Student’s t test was used for intergroup comparisons. For non-normally distributed data, a nonparametric test was used for intergroup comparisons. Intergroup comparisons of categorical variables were performed by Chisquared test. Spearman’s rank correlation coefficient was determined to evaluate the association between parameters. Stepwise multiple linear regression analysis was performed to investigate factors independently associated with the SAGIT scores. All tests were two-sided, and p < 0.05 was considered statistically significant. The area under the receiver operating characteristic curve (AUCROC) was used to evaluate the predicted efficacy of the percent change in serum phosphate. The SPSS software version 20.0 (SPSS, Chicago, IL, USA) was used for all statistical analyses. 4. Results The mean age of the 103 acromegaly patients enrolled was 47 ± 14 years, and 46.6% of the participants were male. However, the mean age in the NRG group was 33 ± 13 years, which was significantly lower than that in the RG group (49 ± 12 years) (P < 0.001). The average preoperative serum P level was 4.87 ± 0.64 mg/dl, and the serum P level was higher in the NRG than in the RG (P = 0.005) (Table 1). Hyperphosphatemia (P > 4.5 mg/dl) occurred in 68.9% of the acromegaly patients at baseline. The SAGITÒ score was higher in the NRG than in the RG (P = 0.001) (Table 1). However, in patients with preoperative serum P > 4.5 mg/dl, no correlation was found between hyperphosphatemia and remission rates (r = 0.187, p = 0.119) (Table 1S). We found a stronger positive correlation between the P level and SAGITÒ scores in acromegaly patients both preoperatively (r = 0.659, p = 0.000) (Fig. 1A) and 1 year postoperatively without remission (r = 0.940, p = 0.000) (Fig. 1I) than between the GH, OGTT-GH, IGF-1, IGBP3, IGF-1/IGBP-3 and the SAGITÒ scores (Fig. 1B-F). Stepwise multiple linear regression analysis showed that pre-operative serum P level was independently associated with the SAGITÒ scores (Table 2). When the preoperative P level was subdivided into hyperphosphatemia (P > 4.5 mg/dl) and normal phosphatemia (P  4.5 mg/dl), the group with hyperphosphatemia showed a good correlation between P levels and SAGITÒ scores (r = 0.553, p = 0.000); however, the correlation was not found in the normal phosphatemia group (Fig. 1G-H). The serum P, GH, OGTT-GH, IGF-1, and IGBP-3 levels decreased significantly after surgical treatment. The GH and OGTT-GH levels achieved early stability (1 month); however, the P, IGF-1 and IGBP3 levels showed a gradual decline from 1 month to 12 months (Fig. 2). From 3-month to 12-month follow-ups, the associations between postoperative biochemical parameter levels and the remission rate and postoperative SAGIT score were analyzed. The serum P level did not show the strongest correlation with the

Please cite this article as: T. Xie, P. Tian, S. Wu et al., Serum phosphate: Does it more closely reflect the true state of acromegaly?, Journal of Clinical Neuroscience, https://doi.org/10.1016/j.jocn.2019.11.012

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T. Xie et al. / Journal of Clinical Neuroscience xxx (xxxx) xxx Table 1 Preoperative clinical and biochemical characteristics of the patients and comparison between the remission and non-remission subgroups.

Age (years) Sex (male/female) BMI (kg/m2) Serum phosphate (mg/dl) SAGIT GH (ng/ml) GH-OGTT (ng/ml) IGF1 (ng/ml) IGBP3 (lg/ml) IGF1/IGBP3

Sum (N = 103)

RG (N = 86)

NRG (N = 17)

P value

47 ± 14 48/55 25.7 ± 3.6 4.87 ± 0.64 13 (12, 15) 15.1 (9.1, 39.5) 7.7 (4.7, 25.4) 765 (620, 961) 6.97 ± 1.47 108 ± 26

49 ± 12 43/43 25.9 ± 3.8 4.79 ± 0.63 13 (11, 14) 12.8 (8.7, 33.7) 7.1 (3.9, 20.0) 761 (610, 912) 6.83 ± 1.45 108 ± 28

33 ± 13 5/12 24.7 ± 2.1 5.26 ± 0.59 15 (14, 16) 40.0 (25.3, 40.0) 40.0 (16.5, 40.0) 893 (661, 1028) 7.57 ± 1.42 112 ± 19

<0.001 0.183 0.252 0.005 0.001 <0.001 <0.001 0.352 0.061 0.521

Sum group: total patients; RG: remission group; NRG: non-remission group; BMI: body mass index; GH: growth hormone; OGTT: oral glucose tolerance test; IGF1: insulinlike growth factor 1; IGBP3: insulin-like growth factor binding protein 3.

Fig. 1. (A-F) Association of the preoperative serum phosphate, GH, OGTT-GH, IGF-1, and IGBP-3 levels, and IGF-1/IGBP-3 ratio with the SAGIT score. (G-H) Association between the preoperative serum phosphate level and SAGIT score in patients with serum phosphate >4.5 mg/dl (hyperphosphatemia) and serum phosphate 4.5 mg/dl group. (I) Association between the serum phosphate level and SAGIT score in patients without remission at 12 months postoperatively. GH, growth hormone; OGTT, oral glucose tolerance test; IGF-1, insulin-like growth factor 1; IGBP-3, insulin-like growth factor binding protein 3.

SAGIT score or remission rate (Table 2S). There were 17 patients (M: 11, F: 6) with discordant GH and IGF-1 levels at 3 months postoperatively. Eleven of them achieved remission at 12 months postoperatively. The AUCROC was used to evaluate the efficacy of the percent change in P in predicting remission in patients with post-

operatively discordant GH and IGF-1 levels. The AUCROC of the percent change in P for predicting remission in patients with postoperatively discordant GH and IGF-1 levels was 0.909 (P = 0.007), which was higher than that of GH, IGF-1, and IGFBP-3 (Fig. 3). We next analyzed the cut-off for the percent change in P for pre-

Please cite this article as: T. Xie, P. Tian, S. Wu et al., Serum phosphate: Does it more closely reflect the true state of acromegaly?, Journal of Clinical Neuroscience, https://doi.org/10.1016/j.jocn.2019.11.012

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Table 2 Stepwise multiple linear regression analysis for the association between preoperative biochemical parameters and preoperative SAGIT.

fore, we recommend 8.12% (sensitivity, 0.833; specificity, 0.818; positive predictive value (PPV), 0.714; negative predictive value (NPV), 0.900) as the cut-off value for predicting remission.

All subjects (n = 103)

Serum phosphorus OGTT-GH BMI

b value

Std bvalue

T value

P value

1.920 0.056 0.104

0.587 0.396 0.164

6.143 4.878 2.074

0.000 0.000 0.041

Adjusted for age and sex. Serum phosphorus, GH, OGTT-GH, IGF-1, IGBP-3, and BMI were included. GH, growth hormone; OGTT, oral glucose tolerance test; IGF-1, insulin-like growth factor 1; IGBP-3, insulin-like growth factor binding protein 3.

dicting remission. When the cut-off for the percent change in P was 12.75%, the Youden index was the highest (Table 3). However, the prediction strategy requires both sensitivity and specificity. There-

5. Discussion The biochemical diagnosis of acromegaly requires the confirmation of persistently elevated serum levels of GH and IGF-1 [11]. Previously, random GH and GH suppression following OGTT were the mainstays of the diagnosis [12]. Then, in the late 1980s, it was discovered that IGF-1 was more strongly correlated with the manifestations of acromegaly than GH [13]. The IGF-1 level usually exhibits a log-linear relationship with the GH levels; however, discordance between the GH and IGF-1 levels persists in daily clinical practice at a rate ranging from 5.4% to 39.5% [14]. This discordance is not just a matter of biochemical discordance; increasing evi-

Fig. 2. Changes in biochemical parameters (A: serum phosphate, B: GH, C: OGTT-GH, D: IGF-1, E: IGBP-3) between preoperatively (Pre-OP), and 1-month, 3-months, and 12months postoperatively. *P < 0.05, **P < 0.01, ***P < 0.001 VS Pre-op group; ##P < 0.01, ## #P < 0.001 VS 1-month group. GH, growth hormone; OGTT, oral glucose tolerance test; IGF-1, insulin-like growth factor 1; IGBP-3, insulin-like growth factor binding protein 3.

Fig. 3. ROC curve for evaluating the efficacy of parameters on predicting remission in patients with postoperatively discordant GH and IGF-1 levels. (A-C) ROC curve for evaluating the efficacy of the percentage change in P, GH, and IGF-1 in predicting remission in patients with postoperatively discordant GH and IGF-1 levels.

Please cite this article as: T. Xie, P. Tian, S. Wu et al., Serum phosphate: Does it more closely reflect the true state of acromegaly?, Journal of Clinical Neuroscience, https://doi.org/10.1016/j.jocn.2019.11.012

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Table 3 The cut-off value of the percentage change of P from preoperative to postoperative 3 months for predicting remission (postoperative 12 months). The sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, positive predictive value, negative predictive value and Youden index under different diagnostic threshold to distinguish remission and non-remission. Cut-off value (%) 12.75 8.12 16.74 4.97 10.55

Sensitivity

Specificity

PLR

NLR

PPV

NPV

Youden index

1 0.833 1 0.667 0.833

0.727 0.818 0.636 0.909 0.727

3.667 4.583 2.750 7.333 3.056

0 0.204 0 0.367 0.229

0.667 0.714 0.600 0.800 0.625

1 0.900 1 0.833 0.889

0.727 0.652 0.636 0.576 0.561

PLR, positive likelihood ratio; NLR, negative likelihood ratio; PPV, positive predictive value; NPV, negative predictive value.

dence has shown that this disease is associated with highly variable clinical, biochemical and neoplastic features [15]. Some patients may harbor localized microadenomas along with typical acromegaly symptoms and comorbidities, and obviously elevated GH and IGF-1 levels, whereas others may have invasive macroadenomas along with insidious symptoms, and moderately elevated GH and IGF-1 levels. Thus, a comprehensive instrument that covers the biochemical, tumoural and clinical aspects of acromegaly should be created. SAGITÒ was generated based on this background [10]. The SAGIT instrument is multidimensional, comprising five key features of acromegaly: signs and symptoms, associated comorbidities, GH levels, IGF-1 levels and tumor profile. This instrument was proceeded by the main thread of the endocrine tumor: the characteristics of the tumor itself; the hormones produced by the tumor; and the changes in the target tissue or organ caused by the hormones. In acromegaly patients with discordance among biochemical, tumoural and clinical features, SAGITÒ may allow a more comprehensive assessment of the disease status. This instrument is focused more on the body’s response to tumors and not merely on the GH/IGF-1 levels mentioned by the guidelines. This tool also focuses on the patient’s complaints and associated comorbidities. Based on the awkward circumstance of discordance between the GH and IGF-1 levels, a search for new markers that can reflect the status of acromegaly comprehensively is expected. Previous studies have shown that high GH levels in acromegaly patients lead to increased renal P reabsorption and hyperphosphatemia [7]. Further perfusion studies in rabbits clearly showed that the P-retaining action of GH is entirely mediated by IGF-1 and takes place in the proximal tube [16]. P is taken up from tubular fluid by apical membrane sodium-phosphate (Na-Pi) cotransporters and IGF-1 directly increases the level of a specific type IIa Na-Pi cotransporter protein in the plasma membrane [9]. These results mean that the serum P level is affected by the GH-IGF-1 axis downstream. This metabolite represents the target organ response to the GH hypersecretion. In a sense, the serum P level may more closely reflect disease activity in acromegaly. In our study, we revealed a higher positive correlation between P levels and SAGITÒ scores both in preoperative acromegaly patients and 1 y postoperative non-remission patients than the correlation among the GH, OGTT-GH, IGF-1, IGBP-3, IGF-1/IGBP-3 and SAGITÒ scores(Table 3-4S). However, when remission was achieved after the operation, the correlation between P levels and SAGITÒ scores declined. This finding is probably due to the acromegaly patients achieving remission and the stimulus for the GH-IGF-1 axis to phosphate metabolism not existing, while the associated comorbidities of acromegaly may persist even after long-term remission. In this study, there was no correlation between hyperphosphatemia and remission rates. This result is not in accordance with that in a previous study [17], which reported that a high serum P levels may be an indicator of a low likelihood of remission onset in acromegaly patients. Larger clinical studies are expected to resolve this debate.

Discordance between GH and IGF-1 also creates a dilemma during postoperative follow-up, and many clinicians are most concerned about which index to follow [5,18,19]. Many doctors choose IGF-1 to guide further monitoring and treatment. Because IGF-1 mediates biological effects, it represents a combination of the integrated effects of GH secretion and GH action. However, others firmly believe that as the tumor produces GH and not IGF1, the GH levels reflects tumor activity and viability and, should therefore be monitored first [19]. In view of our findings, the serum P level may more closely reflect the true state of the disease. We discovered that an 8.12% decrease in P relative to from baseline at 3 months postoperatively may predict remission at 12 months postoperatively. However, an important limitation of the present study is the small number of patients with discordant GH and IGF-1 levels. Multicenter prospective studies should be performed for re-evaluation in the future. 6. Conclusion As a metabolic product affected by the GH/IGF-1 axis, serum P appears to be a more natural value to reflect the disease status of acromegaly comprehensively. When the GH and IGF-1 levels are discordant during follow-up, the perioperative change in the serum P level may be a potential predictor of remission. Evaluation of the serum P level has potential as a tool for monitoring acromegaly patients. Disclosure statement The authors do not have any conflict of interest to declare. Funding This work was supported by the Foundation of China Ministry of Science and Technology (2016YFC0106103). Informed consent Informed consent was obtained from all individual participants included in the study. Appendix A. Supplementary data Supplementary data to this article can be found online at https://doi.org/10.1016/j.jocn.2019.11.012. References [1] Capatina C, Wass JA. 60 years of neuroendocrinology: acromegaly. J Endocrinol 2015;226(2):141–60. [2] Katznelson Laurence. Alterations in body composition in acromegaly. Pituitary 2009;12:136–42. [3] Melmed Shlomo. Acromegaly pathogenesis and treatment. J Clin Invest 2009;119:3189–202.

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Please cite this article as: T. Xie, P. Tian, S. Wu et al., Serum phosphate: Does it more closely reflect the true state of acromegaly?, Journal of Clinical Neuroscience, https://doi.org/10.1016/j.jocn.2019.11.012