World J Surg (2014) 38:2838–2844 DOI 10.1007/s00268-014-2695-8
Aluminum Overload Hampers Symptom Improvement Following Parathyroidectomy for Secondary Hyperparathyroidism Shih-Ping Cheng • Jie-Jen Lee • Tsang-Pai Liu • Han-Hsiang Chen • Chih-Jen Wu • Chien-Liang Liu
Published online: 8 July 2014 Ó Socie´te´ Internationale de Chirurgie 2014
Abstract Background Aluminum overload and accumulation in tissues may lead to skeletal, hematological, and neurological toxicity. The aim of this study was to assess the effects of serum aluminum levels on presentations, postoperative recovery, and symptom improvement in patients undergoing parathyroidectomy for secondary hyperparathyroidism. Methods From 2008 to 2013, all patients with end-stage renal disease undergoing initial parathyroidectomy were included in the study. Serum aluminum level was measured preoperatively and/or within 1 week after surgery. Preoperative and postoperative biochemical profile and symptoms were compared between the low and high aluminum groups. Results A total of 176 patients were included in the study. Of these, 38 (22 %) patients had serum aluminum levels higher than 20 lg/L. A higher percentage of patients in the high aluminum group were on peritoneal dialysis than in the low aluminum group (24 vs. 4 %, p = 0.001). Both
S.-P. Cheng J.-J. Lee T.-P. Liu C.-L. Liu (&) Department of Surgery, Mackay Memorial Hospital, Mackay Medical College, 92, Sec. 2, Zhongshan N. Rd, Taipei 10449, Taiwan e-mail: [email protected] S.-P. Cheng J.-J. Lee T.-P. Liu H.-H. Chen C.-L. Liu Mackay Junior College of Medicine, Nursing, and Management, Taipei, Taiwan S.-P. Cheng J.-J. Lee C.-J. Wu Department of Pharmacology, Graduate Institute of Medical Sciences, Taipei Medical University, Taipei, Taiwan H.-H. Chen C.-J. Wu Department of Nephrology, Mackay Memorial Hospital, Mackay Medical College, Taipei, Taiwan
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groups had similar bone mineral density and changes in biochemical profiles. The preoperative parathyroidectomy assessment of symptoms (PAS) score was not associated with serum aluminum levels (p = 0.349), whereas the postoperative PAS score showed positive association (p = 0.005). There was a negative association between serum aluminum levels and the improvement of total PAS scores (p = 0.001). The high aluminum group had more residual symptoms in three aspects: bone pain (p = 0.038), difficulty getting out of a chair or car (p = 0.045), and pruritus (p = 0.041). Conclusions A high serum aluminum level was associated with reduced symptom improvement in patients undergoing parathyroidectomy for secondary hyperparathyroidism.
Introduction Secondary hyperparathyroidism is the most common abnormality of mineral metabolism in patients with endstage renal disease (ESRD). Phosphate retention, hypocalcemia, and altered vitamin D metabolism contribute to the development of secondary hyperparathyroidism [1]. Phosphate binders, calcitriol analogs, and calcimimetics are common measures used to suppress parathyroid hormone (PTH) levels and minimize associated derangements and complications in mineral metabolism. In some patients, medical therapy is not successful, and parathyroidectomy is indicated to achieve adequate control of secondary hyperparathyroidism. Recently, we have shown that parathyroidectomy effectively alleviates symptoms and improves quality of life in patients with secondary hyperparathyroidism refractory to medical treatment [2]. Phosphate-binding agents are frequently prescribed for ESRD patients who have uncontrolled hyperphosphatemia
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despite dietary phosphorus restriction. Aluminum compounds are potent phosphate binders and historically represented the mainstay treatment for hyperphosphatemia. In the 1990s, it was appreciated that aluminum overload and accumulation in tissues may lead to skeletal, hematological, and neurological toxicity [3]. Therefore, current guidelines recommend avoiding the long-term use of aluminum-containing phosphate binders [4, 5]. Although calcium-based phosphate binders are now frequently used as the initial binder therapy, a positive calcium balance may promote the progression of vascular calcification in patients at risk [6]. A recent meta-analysis suggested that non-calcium-based phosphate binders are associated with a decreased risk of all-cause mortality compared with calcium-based phosphate binders [7]. Calcium-free binders are indispensable in some patients. Based on the guidelines of the National Kidney Foundation Kidney Disease Outcomes Quality Initiative (K/DOQI), serum aluminum levels should be kept below 20 lg/L [4]. In our experience, a few patients referred for parathyroidectomy at our institution were taking aluminum salts because of hypercalcemia, a contraindication to calcium-based phosphate binders. The aim of this study was to evaluate the effects of serum aluminum levels on presentations, postoperative recovery, and symptom improvement in patients undergoing parathyroidectomy for secondary hyperparathyroidism.
Patients and methods This study was approved by the Mackay Memorial Hospital Institutional Review Board (14MMHIS028). From August 2008 to August 2013, a total of 179 consecutive ESRD patients undergoing initial parathyroidectomy for secondary hyperparathyroidism at a tertiary care center were prospectively recorded and constitute our study population. All patients required renal replacement therapy and had biochemically confirmed secondary hyperparathyroidism. Most patients were receiving regular hemodialysis except 15 (8 %) who were receiving regular peritoneal dialysis. The indication for parathyroidectomy was severe hyperparathyroidism associated with hypercalcemia and/or hyperphosphatemia that was refractory to medical therapy [8]. None of the patients presented with clinical signs and symptoms of aluminum toxicity, and a deferoxamine test was not performed. Serum calcium, phosphate, total alkaline phosphatase, albumin, and intact PTH (1–84) were determined preoperatively and during follow-up. When serum albumin level was \4.0 g/dL, serum calcium levels were corrected using the following formula: corrected calcium (mg/dL) = measured total calcium (mg/dL) ? 0.8 9 [4.0—serum albumin (g/dL)].
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Bone mineral density (BMD) at the lumbar spine and hip was measured by dual-energy X-ray absorptiometry. Serum aluminum level was measured preoperatively and/or within 1 week after surgery. Aluminum determinations were performed with an XplorAA atomic absorption spectrophotometer (GBC Scientific Equipment, Braeside, VIC, Australia). Blood samples were stored at 4 °C and were analyzed within 2 weeks of collection. Both neck ultrasonography and technetium sestamibi scan were performed before surgery. All patients underwent bilateral cervical exploration followed by subtotal or total parathyroidectomy plus autotransplantation [9]. Our goal was to control intact PTH levels to the target range of 150–300 pg/mL based on the K/DOQI guidelines [4]. Symptom assessment was carried out with the parathyroidectomy assessment of symptoms (PAS) questionnaire preoperatively and 6–12 months after surgery [2]. This patient self-report questionnaire included 13 disease-specific items (pain in the bones, feeling tired easily, mood swings, feeling ‘blue’ or depressed, pain in the abdomen, feeling weak, feeling irritable, pain in the joints, being forgetful, difficulty getting out of a chair or car, headaches, itchy skin, being thirsty) using a visual analog scale ranging from 0 (not experiencing the symptoms) to 100 (experiencing the most extreme aspects of the symptoms). A total PAS score was obtained from the sum of the 13 parameters. Using a standard forward–backward translation procedure, the English language version of the questionnaire was translated into the Taiwan Chinese version, which was tested and validated in our previous study [2]. The data were analyzed using STATA 11.0 (Stata Corp., College Station, TX, USA). All data are reported as means ± standard deviations. Where distributions appeared non-normal, we used natural log transformations to normalize the skewed distributions. Student’s t test (paired or unpaired) was used to evaluate differences between groups. Categorical data were compared using Fisher’s exact test or Chi squared test, as appropriate. Simple regression analysis was used to assess the linear relationship between parameters. A multivariate logistic regression analysis was performed to identify parameters associated with no improvement in the total PAS score following parathyroidectomy. A sensitivity analysis was conducted to control for the impact of preoperative serum calcium levels. All statistical tests were two-sided, and statistical significance was determined as p \ 0.05.
Results During the study period, 179 ESRD patients were identified who underwent initial parathyroidectomy. Three patients who had no serum aluminum determination were excluded
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Fig. 1 Distribution of serum aluminum levels in 176 patients undergoing parathyroidectomy for secondary hyperparathyroidism
from further analysis. For the remaining 176 patients, the mean age was 55 ± 11 years. A total of 103 (59 %) patients were female. The mean duration of dialysis before surgery was 9.7 ± 5.1 years. The distribution of serum aluminum levels is shown in Fig. 1. In all, 71 (40 %) patients had both preoperative and immediate postoperative serum aluminum levels available. Parathyroidectomy did not influence the serum aluminum levels in the short term (13.2 ± 5.8 lg/L preoperatively and 12.7 ± 5.1 lg/L postoperatively, p = 0.384). As recommended by K/DOQI guidelines [4], patients were classified as high aluminum (C20 lg/L) or low aluminum (\20 lg/L). The mean serum aluminum level was 11.9 ± 4.0 lg/L (range 2.8–19.7) and 26.6 ± 6.5 lg/L (range 20.2–48.8) for the low and high aluminum group, respectively. No difference in age, gender, and body mass index was observed between the groups (Table 1). A higher percentage of patients in the high aluminum group were on peritoneal dialysis than in the low aluminum group (24 vs. 4 %, p = 0.001). Other biochemical parameters, including BMD, calcium, phosphorus, alkaline phosphatase, and intact PTH levels were comparable between the groups. Serum aluminum level was not associated with intact PTH levels (p = 0.376). Preoperatively, the mean total PAS score in the high aluminum group was 470 ± 212, comparable to that of the low aluminum group (486 ± 270, p = 0.764). There was no difference in 13 symptom items between the groups (Fig. 2). Serum aluminum level was not associated with total PAS scores (p = 0.349). Therefore, it appears that there was no association between serum aluminum levels and biochemical parameters or symptom presentations in patients with secondary hyperparathyroidism before surgery. As expected, serum calcium, phosphorus, alkaline phosphatase, and intact PTH levels dropped significantly after parathyroidectomy (all p \ 0.001) in both groups. The majority of patients underwent total parathyroidectomy and
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autotransplantation. In all, 43 (24 %) patients had concurrent thyroidectomy, including five for thyroid cancer. The length of postoperative hospital stay was 4.4 ± 2.6 days (range 2–20). Both groups showed similar postoperative recovery. During follow-up, biochemical parameters were comparable between the groups (Table 2). In the low aluminum group, the total PAS score dropped from 486 ± 270 to 298 ± 151 after parathyroidectomy (p \ 0.001). In the high aluminum group, the total PAS score also reduced significantly (470 ± 212 to 363 ± 167, p = 0.044). However, as shown in Fig. 3, a significant difference between the two groups was observed in three symptom items: bone pain (p = 0.038), difficulty getting out of a chair or car (p = 0.045), and pruritus (p = 0.041). Of note, serum aluminum level was positively associated with postoperative total PAS scores (adjusted r2 = 0.122, p = 0.005). There was a negative association between serum aluminum levels and the improvement of total PAS scores (adjusted r2 = 0.162, p = 0.001). To determine how preoperative calcium levels affected our findings, we performed a sensitivity analysis that only included patients with hypercalcemia (corrected calcium levels above 10.2 mg/dL). In general, these results confirmed the primary analyses. Among 128 patients who had hypercalcemia, there was a significant reduction of the total PAS score in the low aluminum group (p \ 0.001), whereas the difference was borderline in the high aluminum group (p = 0.051). Serum aluminum levels was significantly associated with the decrease in total PAS scores (adjusted r2 = 0.125, p = 0.012). For patients who had no hypercalcemia preoperatively, a significant association remained between serum aluminum levels and the change in total PAS scores (adjusted r2 = 0.232, p = 0.047). To explore possible confounding of the effect of the high aluminum levels on hyperparathyroidism-related symptoms, we identified 20 (11 %) patients exhibiting no improvement in PAS scores following parathyroidectomy (higher postoperative total PAS scores than preoperative scores). Variables that met statistical significance on univariate analysis were included in the multivariate model, in addition to variables that were previously shown to have an effect on the decrease in PAS score [2]. As shown in Table 3, a high serum aluminum level was identified as a significant independent predictor of no improvement in PAS scores postoperatively (odds ratio 4.36; 95 % confidence interval 1.08–17.62; p = 0.039). In addition, the analysis revealed that a higher preoperative PAS score was associated with a higher likelihood of improvement in the total PAS score.
Discussion The use of phosphate-binding agents among dialysis patients was associated with lower mortality [10].
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Table 1 Characteristics of 176 patients with secondary hyperparathyroidism Low aluminum (n = 138)
High aluminum (n = 38)
p value
Age (years)
55 ± 11
54 ± 11
0.472
Female (n)
79 (57 %)
24 (63 %)
0.513
Hemodialysis (n)
132 (96 %)
29 (76 %)
0.001
Duration of dialysis (years)
10.0 ± 5.0
8.9 ± 5.5
0.241
Body weight (kg)
60 ± 12
62 ± 14
0.357
BMI (kg/m2)
23.4 ± 4.0
24.4 ± 4.0
0.184
Preop BMD (T score)
–1.6 ± 1.3
–1.4 ± 1.4
0.522
Preop BMD (Z score)
–0.6 ± 0.9
–0.5 ± 1.1
0.598
Preop hemoglobin (g/dL)
10.9 ± 1.7
10.8 ± 1.8
0.564
Preop albumin (g/dL)
4.2 ± 0.4
4.2 ± 0.4
0.424
Preop corrected calcium (mg/dL) Preop phosphorus (mg/dL)
10.6 ± 0.8 6.2 ± 1.4
10.7 ± 0.9 6.1 ± 1.0
0.299 0.663
Calcium–phosphorus product (mg2/dL2)
65.3 ± 14.8
64.9 ± 9.2
0.858
Preop alkaline phosphatase (IU/L)
292 ± 268
320 ± 309
0.410a
Preop PTH (pg/mL)
1,384 ± 475
1,358 ± 380
0.754
BMD bone mineral density, BMI body mass index, preop preoperative, PTH parathyroid hormone a
Analysis after logarithmic transformation
Fig. 2 Preoperative parathyroidectomy assessment of symptoms (PAS) scores in patients with secondary hyperparathyroidism. Error bars represent 95 % confidence intervals. Al aluminum
Commonly used calcium salts and calcium-free binders (sevelamer and lanthanum carbonate) are all effective in lowering serum phosphorus levels. Nonetheless, accumulating evidence suggests that calcium-free binders provide benefits in all-cause mortality [7, 11]. In Taiwan, a National Health Insurance program has been in effect since 1995 [12]. Although National Health Insurance is a government-run, comprehensive health insurance program, some medications (sevelamer, lanthanum carbonate, and calcimimetics) are currently not covered under the National
Health Insurance system. For patients who are not suitable for calcium-based phosphate binders and cannot afford sevelamer or lanthanum carbonate, aluminum-containing phosphate binders are a reasonable alternative. In our study, we found that patients with high serum aluminum levels exhibited a higher ratio of peritoneal dialysis to hemodialysis. Theoretically, total dialytic phosphorus removal is 800–1,000 mg per session or about 300 mg/day by hemodialysis; whereas a slightly better 423 mg/day could be achieved by peritoneal dialysis [13]. In our
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Table 2 Perioperative parameters and postoperative biochemical profile after parathyroidectomy for secondary hyperparathyroidism Low aluminum (n = 138)
High aluminum (n = 38)
p value
Subtotal parathyroidectomy (n)
21 (15 %)
7 (18 %)
0.622
Concurrent thyroidectomy (n)
31 (22 %)
12 (32 %)
0.287
Removed parathyroid weight (mg)
2,938 ± 1,753
3,590 ± 3,881
0.970a
Length of postop stay (days)
4.3 ± 2.5
4.8 ± 2.7
0.309a
Postop corrected calcium (mg/dL)
8.1 ± 1.1
8.0 ± 1.1
0.700
Postop phosphorus (mg/dL)
4.6 ± 1.1
4.5 ± 1.1
0.408
Calcium-phosphorus product (mg2/dL2)
37.6 ± 11.1
35.6 ± 9.9
0.335
Postop alkaline phosphatase (IU/L)
260 ± 234
281 ± 287
0.501a
Postop parathyroid hormone (pg/mL)
135 ± 225
157 ± 225
0.226a
Postop postoperative a
Analysis after logarithmic transformation
Fig. 3 Postoperative parathyroidectomy assessment of symptoms (PAS) scores in patients with secondary hyperparathyroidism. Error bars represent 95 % confidence intervals. *p \ 0.05, Al aluminum
Table 3 Factors associated with no improvement in total parathyroidectomy assessment of symptoms scores following parathyroidectomy Odds ratio
95 % CI
p value
Body mass index (kg/m2)
1.26
1.00–1.60
Bone mineral density (T score)
0.66
0.37–1.19
0.168
Preop Ca–P product (mg2/dL2) Preoperative PAS score
0.98 0.99
0.93–1.04 0.99–1.00
0.574 0.001
High serum aluminum level
4.36
1.08–17.62
0.039
0.053
CI confidence interval, PAS parathyroidectomy assessment of symptoms, Preop preoperative
patients, there was no significant difference between the dialysis modalities in calcium-phosphorus product and intact PTH levels. However, patients receiving peritoneal
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dialysis were younger at operation (mean 48 vs. 55 years, p = 0.020). In addition to referral bias, this discrepancy needs further clarification in the future. Sources of aluminum overload include medicines containing aluminum, the water used for dialysis, and other environmental and industrial sources. The major aluminum toxicities are central nervous system toxicity, impairment of bone mineralization, and microcytosis [3]. Aluminum toxicity is probably the major factor in the pathogenesis of dialysis dementia, a unique neurologic complication of ESRD associated with chronic dialysis [14]. In addition, aluminum overload leads to aluminum bone disease (adynamic bone or osteomalacia) and is associated with a poor response to calcitriol therapy [15]. Musculoskeletal pain, arthralgia, and proximal muscle weakness are common
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[16]. Our data are in concordance with these observations and showed that patients with high serum aluminum levels reported more residual symptoms after parathyroidectomy. The K/DOQI guidelines suggest that a deferoxamine test should be performed when serum aluminum levels are between 60 and 200 lg/L [4]. The test is conducted by infusing 5 mg/kg of deferoxamine, an iron-chelating agent, at the end of a dialysis session. Serum aluminum levels are measured before deferoxamine infusion and 2 days later, before the next dialysis session. When the increment of serum aluminum is [50 lg/L, the test is considered positive, and deferoxamine therapy and high-efficiency dialysis should be given. Considering that parathyroidectomy may enhance aluminum deposition on the bone surface [17], our policy is not to perform parathyroidectomy in patients with a serum aluminum level above 60 lg/L. Aluminum overload may also contribute to microcytic anemia [18]. Nonetheless, there was no difference in hemoglobin levels between the low and high aluminum groups. Uremic pruritus is a common complaint of ESRD patients and can markedly affect a patient’s quality of life [19]. Pathophysiology of pruritus includes uremic alterations (particularly high calcium-phosphorus product), inflammation, opioid system, and neuropathy [20]. We noted that the high aluminum group had persistent pruritus after parathyroidectomy compared with the low aluminum group, although there was no difference between the groups in the extent of pruritus before surgery. In line with our observation, Friga et al. [21] reported that hemodialysis patients with pruritus had higher serum aluminum concentrations, and the intensity of pruritus was related to the aluminum concentration. The mechanisms of refractory pruritus after parathyroidectomy in patients with high aluminum levels are little known. The most severe cases of aluminum toxicity occur in patients who have contamination of dialysate with aluminum; however, aluminumbased binders may also play a role. Although aluminum salts are the most ‘potent’ phosphate binders, the safe dose of aluminum-based binders is yet to be determined. Several new phosphate-lowering compounds are under development [22]. Based on our results, we discourage patients from taking aluminum-containing phosphate binders. Before parathyroidectomy, patients with higher serum aluminum levels should be informed of the possibility of symptom persistence. We must acknowledge several study limitations. Bone biopsy was not performed in our patients. The evaluation and definitive diagnosis of renal osteodystrophy require a bone biopsy, which is also considered the gold standard for the diagnosis of aluminum bone disease [4]. Furthermore, long-term changes in BMD were not available in our study. Most patients were followed up at local dialysis clinic where BMD testing is infrequent. Finally, we did not
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examine longitudinal changes of serum aluminum levels. Our patients typically discontinue the use of phosphate binders after parathyroidectomy. A decrease in serial analysis of blood aluminum levels may reflect reduced ingestion of aluminum salts or enhanced bone aluminum accumulation.
Conclusion The present study demonstrated that ESRD patients with low or high serum aluminum levels had similar preoperative symptomatology and perioperative biochemical changes. However, patients with high serum aluminum levels had more residual symptoms after parathyroidectomy. Exposure to aluminum should be limited, especially among patients with refractory hyperparathyroidism who are scheduled for parathyroidectomy.
Conflict of interest The authors have no conflict of interest to declare.
References 1. Kumar R, Thompson JR (2011) The regulation of parathyroid hormone secretion and synthesis. J Am Soc Nephrol 22:216–224 2. Cheng SP, Lee JJ, Liu TP et al (2014) Parathyroidectomy improves symptomatology and quality of life in patients with secondary hyperparathyroidism. Surgery 155:320–328 3. Jeffery EH, Abreo K, Burgess E et al (1996) Systemic aluminum toxicity: effects on bone, hematopoietic tissue, and kidney. J Toxicol Environ Health 48:649–665 4. National Kidney Foundation (2003) K/DOQI clinical practice guidelines for bone metabolism and disease in chronic kidney disease. Am J Kidney Dis 42:S1–S201 5. Kidney Disease Improving Global Outcomes (KDIGO) CKDMBD Work Group (2009) KDIGO clinical practice guideline for the diagnosis, evaluation, prevention, and treatment of chronic kidney disease-mineral and bone disorder (CKD-MBD). Kidney Int Suppl 113:S1–S130 6. Block GA, Wheeler DC, Persky MS et al (2012) Effects of phosphate binders in moderate CKD. J Am Soc Nephrol 23:1407–1415 7. Jamal SA, Vandermeer B, Raggi P et al (2013) Effect of calciumbased versus non-calcium-based phosphate binders on mortality in patients with chronic kidney disease: an updated systematic review and meta-analysis. Lancet 382:1268–1277 8. Cheng SP, Liu CL, Chen HH et al (2009) Prolonged hospital stay after parathyroidectomy for secondary hyperparathyroidism. World J Surg 33:72–79. doi:10.1007/s00268-008-9787-2 9. Cheng SP, Yang TL, Lee JJ et al (2011) Gender differences among patients with secondary hyperparathyroidism undergoing parathyroidectomy. J Surg Res 168:82–87 10. Lopes AA, Tong L, Thumma J et al (2012) Phosphate binder use and mortality among hemodialysis patients in the dialysis outcomes and practice patterns study (DOPPS): evaluation of possible confounding by nutritional status. Am J Kidney Dis 60:90–101
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2844 11. Di Iorio B, Bellasi A, Russo D, INDEPENDENT Study Investigators (2012) Mortality in kidney disease patients treated with phosphate binders: a randomized study. Clin J Am Soc Nephrol 7:487–493 12. Lee CH, Lee YC (2003) Surgery in Taiwan. Arch Surg 138:922–927 13. Uribarri J (2007) Phosphorus homeostasis in normal health and in chronic kidney disease patients with special emphasis on dietary phosphorus intake. Semin Dial 20:295–301 14. Alfrey AC, LeGendre GR, Kaehny WD (1976) The dialysis encephalopathy syndrome. Possible aluminum intoxication. N Engl J Med 294:184–188 15. Ott SM, Maloney NA, Coburn JW et al (1982) The prevalence of bone aluminum deposition in renal osteodystrophy and its relation to the response to calcitriol therapy. N Engl J Med 307:709–713 16. Coburn JW, Norris KC (1986) Diagnosis of aluminum-related bone disease and treatment of aluminum toxicity with deferoxamine. Semin Nephrol 6(4 Suppl 1):12–21
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World J Surg (2014) 38:2838–2844 17. Andress DL, Ott SM, Maloney NA et al (1985) Effect of parathyroidectomy on bone aluminum accumulation in chronic renal failure. N Engl J Med 312:468–473 18. O’Hare JA, Murnaghan DJ (1982) Reversal of aluminum-induced hemodialysis anemia by a low-aluminum dialysate. N Engl J Med 306:654–656 19. Narita I, Alchi B, Omori K et al (2006) Etiology and prognostic significance of severe uremic pruritus in chronic hemodialysis patients. Kidney Int 69:1626–1632 20. Manenti L, Tansinda P, Vaglio A (2009) Uraemic pruritus: clinical characteristics, pathophysiology and treatment. Drugs 69:251–263 21. Friga V, Linos A, Linos DA (1997) Is aluminum toxicity responsible for uremic pruritus in chronic hemodialysis patients? Nephron 75:48–53 22. Ketteler M, Biggar PH (2013) Use of phosphate binders in chronic kidney disease. Curr Opin Nephrol Hypertens 22:413–420
Aluminum Overload Hampers Symptom Improvement Following Parathyroidectomy for Secondary Hyperparathyroidism Shih-Ping Cheng • Jie-Jen Lee • Tsang-Pai Liu • Han-Hsiang Chen • Chih-Jen Wu • Chien-Liang Liu
Published online: 8 July 2014 Ó Socie´te´ Internationale de Chirurgie 2014
Abstract Background Aluminum overload and accumulation in tissues may lead to skeletal, hematological, and neurological toxicity. The aim of this study was to assess the effects of serum aluminum levels on presentations, postoperative recovery, and symptom improvement in patients undergoing parathyroidectomy for secondary hyperparathyroidism. Methods From 2008 to 2013, all patients with end-stage renal disease undergoing initial parathyroidectomy were included in the study. Serum aluminum level was measured preoperatively and/or within 1 week after surgery. Preoperative and postoperative biochemical profile and symptoms were compared between the low and high aluminum groups. Results A total of 176 patients were included in the study. Of these, 38 (22 %) patients had serum aluminum levels higher than 20 lg/L. A higher percentage of patients in the high aluminum group were on peritoneal dialysis than in the low aluminum group (24 vs. 4 %, p = 0.001). Both
S.-P. Cheng J.-J. Lee T.-P. Liu C.-L. Liu (&) Department of Surgery, Mackay Memorial Hospital, Mackay Medical College, 92, Sec. 2, Zhongshan N. Rd, Taipei 10449, Taiwan e-mail: [email protected] S.-P. Cheng J.-J. Lee T.-P. Liu H.-H. Chen C.-L. Liu Mackay Junior College of Medicine, Nursing, and Management, Taipei, Taiwan S.-P. Cheng J.-J. Lee C.-J. Wu Department of Pharmacology, Graduate Institute of Medical Sciences, Taipei Medical University, Taipei, Taiwan H.-H. Chen C.-J. Wu Department of Nephrology, Mackay Memorial Hospital, Mackay Medical College, Taipei, Taiwan
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groups had similar bone mineral density and changes in biochemical profiles. The preoperative parathyroidectomy assessment of symptoms (PAS) score was not associated with serum aluminum levels (p = 0.349), whereas the postoperative PAS score showed positive association (p = 0.005). There was a negative association between serum aluminum levels and the improvement of total PAS scores (p = 0.001). The high aluminum group had more residual symptoms in three aspects: bone pain (p = 0.038), difficulty getting out of a chair or car (p = 0.045), and pruritus (p = 0.041). Conclusions A high serum aluminum level was associated with reduced symptom improvement in patients undergoing parathyroidectomy for secondary hyperparathyroidism.
Introduction Secondary hyperparathyroidism is the most common abnormality of mineral metabolism in patients with endstage renal disease (ESRD). Phosphate retention, hypocalcemia, and altered vitamin D metabolism contribute to the development of secondary hyperparathyroidism [1]. Phosphate binders, calcitriol analogs, and calcimimetics are common measures used to suppress parathyroid hormone (PTH) levels and minimize associated derangements and complications in mineral metabolism. In some patients, medical therapy is not successful, and parathyroidectomy is indicated to achieve adequate control of secondary hyperparathyroidism. Recently, we have shown that parathyroidectomy effectively alleviates symptoms and improves quality of life in patients with secondary hyperparathyroidism refractory to medical treatment [2]. Phosphate-binding agents are frequently prescribed for ESRD patients who have uncontrolled hyperphosphatemia
World J Surg (2014) 38:2838–2844
despite dietary phosphorus restriction. Aluminum compounds are potent phosphate binders and historically represented the mainstay treatment for hyperphosphatemia. In the 1990s, it was appreciated that aluminum overload and accumulation in tissues may lead to skeletal, hematological, and neurological toxicity [3]. Therefore, current guidelines recommend avoiding the long-term use of aluminum-containing phosphate binders [4, 5]. Although calcium-based phosphate binders are now frequently used as the initial binder therapy, a positive calcium balance may promote the progression of vascular calcification in patients at risk [6]. A recent meta-analysis suggested that non-calcium-based phosphate binders are associated with a decreased risk of all-cause mortality compared with calcium-based phosphate binders [7]. Calcium-free binders are indispensable in some patients. Based on the guidelines of the National Kidney Foundation Kidney Disease Outcomes Quality Initiative (K/DOQI), serum aluminum levels should be kept below 20 lg/L [4]. In our experience, a few patients referred for parathyroidectomy at our institution were taking aluminum salts because of hypercalcemia, a contraindication to calcium-based phosphate binders. The aim of this study was to evaluate the effects of serum aluminum levels on presentations, postoperative recovery, and symptom improvement in patients undergoing parathyroidectomy for secondary hyperparathyroidism.
Patients and methods This study was approved by the Mackay Memorial Hospital Institutional Review Board (14MMHIS028). From August 2008 to August 2013, a total of 179 consecutive ESRD patients undergoing initial parathyroidectomy for secondary hyperparathyroidism at a tertiary care center were prospectively recorded and constitute our study population. All patients required renal replacement therapy and had biochemically confirmed secondary hyperparathyroidism. Most patients were receiving regular hemodialysis except 15 (8 %) who were receiving regular peritoneal dialysis. The indication for parathyroidectomy was severe hyperparathyroidism associated with hypercalcemia and/or hyperphosphatemia that was refractory to medical therapy [8]. None of the patients presented with clinical signs and symptoms of aluminum toxicity, and a deferoxamine test was not performed. Serum calcium, phosphate, total alkaline phosphatase, albumin, and intact PTH (1–84) were determined preoperatively and during follow-up. When serum albumin level was \4.0 g/dL, serum calcium levels were corrected using the following formula: corrected calcium (mg/dL) = measured total calcium (mg/dL) ? 0.8 9 [4.0—serum albumin (g/dL)].
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Bone mineral density (BMD) at the lumbar spine and hip was measured by dual-energy X-ray absorptiometry. Serum aluminum level was measured preoperatively and/or within 1 week after surgery. Aluminum determinations were performed with an XplorAA atomic absorption spectrophotometer (GBC Scientific Equipment, Braeside, VIC, Australia). Blood samples were stored at 4 °C and were analyzed within 2 weeks of collection. Both neck ultrasonography and technetium sestamibi scan were performed before surgery. All patients underwent bilateral cervical exploration followed by subtotal or total parathyroidectomy plus autotransplantation [9]. Our goal was to control intact PTH levels to the target range of 150–300 pg/mL based on the K/DOQI guidelines [4]. Symptom assessment was carried out with the parathyroidectomy assessment of symptoms (PAS) questionnaire preoperatively and 6–12 months after surgery [2]. This patient self-report questionnaire included 13 disease-specific items (pain in the bones, feeling tired easily, mood swings, feeling ‘blue’ or depressed, pain in the abdomen, feeling weak, feeling irritable, pain in the joints, being forgetful, difficulty getting out of a chair or car, headaches, itchy skin, being thirsty) using a visual analog scale ranging from 0 (not experiencing the symptoms) to 100 (experiencing the most extreme aspects of the symptoms). A total PAS score was obtained from the sum of the 13 parameters. Using a standard forward–backward translation procedure, the English language version of the questionnaire was translated into the Taiwan Chinese version, which was tested and validated in our previous study [2]. The data were analyzed using STATA 11.0 (Stata Corp., College Station, TX, USA). All data are reported as means ± standard deviations. Where distributions appeared non-normal, we used natural log transformations to normalize the skewed distributions. Student’s t test (paired or unpaired) was used to evaluate differences between groups. Categorical data were compared using Fisher’s exact test or Chi squared test, as appropriate. Simple regression analysis was used to assess the linear relationship between parameters. A multivariate logistic regression analysis was performed to identify parameters associated with no improvement in the total PAS score following parathyroidectomy. A sensitivity analysis was conducted to control for the impact of preoperative serum calcium levels. All statistical tests were two-sided, and statistical significance was determined as p \ 0.05.
Results During the study period, 179 ESRD patients were identified who underwent initial parathyroidectomy. Three patients who had no serum aluminum determination were excluded
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Fig. 1 Distribution of serum aluminum levels in 176 patients undergoing parathyroidectomy for secondary hyperparathyroidism
from further analysis. For the remaining 176 patients, the mean age was 55 ± 11 years. A total of 103 (59 %) patients were female. The mean duration of dialysis before surgery was 9.7 ± 5.1 years. The distribution of serum aluminum levels is shown in Fig. 1. In all, 71 (40 %) patients had both preoperative and immediate postoperative serum aluminum levels available. Parathyroidectomy did not influence the serum aluminum levels in the short term (13.2 ± 5.8 lg/L preoperatively and 12.7 ± 5.1 lg/L postoperatively, p = 0.384). As recommended by K/DOQI guidelines [4], patients were classified as high aluminum (C20 lg/L) or low aluminum (\20 lg/L). The mean serum aluminum level was 11.9 ± 4.0 lg/L (range 2.8–19.7) and 26.6 ± 6.5 lg/L (range 20.2–48.8) for the low and high aluminum group, respectively. No difference in age, gender, and body mass index was observed between the groups (Table 1). A higher percentage of patients in the high aluminum group were on peritoneal dialysis than in the low aluminum group (24 vs. 4 %, p = 0.001). Other biochemical parameters, including BMD, calcium, phosphorus, alkaline phosphatase, and intact PTH levels were comparable between the groups. Serum aluminum level was not associated with intact PTH levels (p = 0.376). Preoperatively, the mean total PAS score in the high aluminum group was 470 ± 212, comparable to that of the low aluminum group (486 ± 270, p = 0.764). There was no difference in 13 symptom items between the groups (Fig. 2). Serum aluminum level was not associated with total PAS scores (p = 0.349). Therefore, it appears that there was no association between serum aluminum levels and biochemical parameters or symptom presentations in patients with secondary hyperparathyroidism before surgery. As expected, serum calcium, phosphorus, alkaline phosphatase, and intact PTH levels dropped significantly after parathyroidectomy (all p \ 0.001) in both groups. The majority of patients underwent total parathyroidectomy and
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autotransplantation. In all, 43 (24 %) patients had concurrent thyroidectomy, including five for thyroid cancer. The length of postoperative hospital stay was 4.4 ± 2.6 days (range 2–20). Both groups showed similar postoperative recovery. During follow-up, biochemical parameters were comparable between the groups (Table 2). In the low aluminum group, the total PAS score dropped from 486 ± 270 to 298 ± 151 after parathyroidectomy (p \ 0.001). In the high aluminum group, the total PAS score also reduced significantly (470 ± 212 to 363 ± 167, p = 0.044). However, as shown in Fig. 3, a significant difference between the two groups was observed in three symptom items: bone pain (p = 0.038), difficulty getting out of a chair or car (p = 0.045), and pruritus (p = 0.041). Of note, serum aluminum level was positively associated with postoperative total PAS scores (adjusted r2 = 0.122, p = 0.005). There was a negative association between serum aluminum levels and the improvement of total PAS scores (adjusted r2 = 0.162, p = 0.001). To determine how preoperative calcium levels affected our findings, we performed a sensitivity analysis that only included patients with hypercalcemia (corrected calcium levels above 10.2 mg/dL). In general, these results confirmed the primary analyses. Among 128 patients who had hypercalcemia, there was a significant reduction of the total PAS score in the low aluminum group (p \ 0.001), whereas the difference was borderline in the high aluminum group (p = 0.051). Serum aluminum levels was significantly associated with the decrease in total PAS scores (adjusted r2 = 0.125, p = 0.012). For patients who had no hypercalcemia preoperatively, a significant association remained between serum aluminum levels and the change in total PAS scores (adjusted r2 = 0.232, p = 0.047). To explore possible confounding of the effect of the high aluminum levels on hyperparathyroidism-related symptoms, we identified 20 (11 %) patients exhibiting no improvement in PAS scores following parathyroidectomy (higher postoperative total PAS scores than preoperative scores). Variables that met statistical significance on univariate analysis were included in the multivariate model, in addition to variables that were previously shown to have an effect on the decrease in PAS score [2]. As shown in Table 3, a high serum aluminum level was identified as a significant independent predictor of no improvement in PAS scores postoperatively (odds ratio 4.36; 95 % confidence interval 1.08–17.62; p = 0.039). In addition, the analysis revealed that a higher preoperative PAS score was associated with a higher likelihood of improvement in the total PAS score.
Discussion The use of phosphate-binding agents among dialysis patients was associated with lower mortality [10].
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Table 1 Characteristics of 176 patients with secondary hyperparathyroidism Low aluminum (n = 138)
High aluminum (n = 38)
p value
Age (years)
55 ± 11
54 ± 11
0.472
Female (n)
79 (57 %)
24 (63 %)
0.513
Hemodialysis (n)
132 (96 %)
29 (76 %)
0.001
Duration of dialysis (years)
10.0 ± 5.0
8.9 ± 5.5
0.241
Body weight (kg)
60 ± 12
62 ± 14
0.357
BMI (kg/m2)
23.4 ± 4.0
24.4 ± 4.0
0.184
Preop BMD (T score)
–1.6 ± 1.3
–1.4 ± 1.4
0.522
Preop BMD (Z score)
–0.6 ± 0.9
–0.5 ± 1.1
0.598
Preop hemoglobin (g/dL)
10.9 ± 1.7
10.8 ± 1.8
0.564
Preop albumin (g/dL)
4.2 ± 0.4
4.2 ± 0.4
0.424
Preop corrected calcium (mg/dL) Preop phosphorus (mg/dL)
10.6 ± 0.8 6.2 ± 1.4
10.7 ± 0.9 6.1 ± 1.0
0.299 0.663
Calcium–phosphorus product (mg2/dL2)
65.3 ± 14.8
64.9 ± 9.2
0.858
Preop alkaline phosphatase (IU/L)
292 ± 268
320 ± 309
0.410a
Preop PTH (pg/mL)
1,384 ± 475
1,358 ± 380
0.754
BMD bone mineral density, BMI body mass index, preop preoperative, PTH parathyroid hormone a
Analysis after logarithmic transformation
Fig. 2 Preoperative parathyroidectomy assessment of symptoms (PAS) scores in patients with secondary hyperparathyroidism. Error bars represent 95 % confidence intervals. Al aluminum
Commonly used calcium salts and calcium-free binders (sevelamer and lanthanum carbonate) are all effective in lowering serum phosphorus levels. Nonetheless, accumulating evidence suggests that calcium-free binders provide benefits in all-cause mortality [7, 11]. In Taiwan, a National Health Insurance program has been in effect since 1995 [12]. Although National Health Insurance is a government-run, comprehensive health insurance program, some medications (sevelamer, lanthanum carbonate, and calcimimetics) are currently not covered under the National
Health Insurance system. For patients who are not suitable for calcium-based phosphate binders and cannot afford sevelamer or lanthanum carbonate, aluminum-containing phosphate binders are a reasonable alternative. In our study, we found that patients with high serum aluminum levels exhibited a higher ratio of peritoneal dialysis to hemodialysis. Theoretically, total dialytic phosphorus removal is 800–1,000 mg per session or about 300 mg/day by hemodialysis; whereas a slightly better 423 mg/day could be achieved by peritoneal dialysis [13]. In our
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Table 2 Perioperative parameters and postoperative biochemical profile after parathyroidectomy for secondary hyperparathyroidism Low aluminum (n = 138)
High aluminum (n = 38)
p value
Subtotal parathyroidectomy (n)
21 (15 %)
7 (18 %)
0.622
Concurrent thyroidectomy (n)
31 (22 %)
12 (32 %)
0.287
Removed parathyroid weight (mg)
2,938 ± 1,753
3,590 ± 3,881
0.970a
Length of postop stay (days)
4.3 ± 2.5
4.8 ± 2.7
0.309a
Postop corrected calcium (mg/dL)
8.1 ± 1.1
8.0 ± 1.1
0.700
Postop phosphorus (mg/dL)
4.6 ± 1.1
4.5 ± 1.1
0.408
Calcium-phosphorus product (mg2/dL2)
37.6 ± 11.1
35.6 ± 9.9
0.335
Postop alkaline phosphatase (IU/L)
260 ± 234
281 ± 287
0.501a
Postop parathyroid hormone (pg/mL)
135 ± 225
157 ± 225
0.226a
Postop postoperative a
Analysis after logarithmic transformation
Fig. 3 Postoperative parathyroidectomy assessment of symptoms (PAS) scores in patients with secondary hyperparathyroidism. Error bars represent 95 % confidence intervals. *p \ 0.05, Al aluminum
Table 3 Factors associated with no improvement in total parathyroidectomy assessment of symptoms scores following parathyroidectomy Odds ratio
95 % CI
p value
Body mass index (kg/m2)
1.26
1.00–1.60
Bone mineral density (T score)
0.66
0.37–1.19
0.168
Preop Ca–P product (mg2/dL2) Preoperative PAS score
0.98 0.99
0.93–1.04 0.99–1.00
0.574 0.001
High serum aluminum level
4.36
1.08–17.62
0.039
0.053
CI confidence interval, PAS parathyroidectomy assessment of symptoms, Preop preoperative
patients, there was no significant difference between the dialysis modalities in calcium-phosphorus product and intact PTH levels. However, patients receiving peritoneal
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dialysis were younger at operation (mean 48 vs. 55 years, p = 0.020). In addition to referral bias, this discrepancy needs further clarification in the future. Sources of aluminum overload include medicines containing aluminum, the water used for dialysis, and other environmental and industrial sources. The major aluminum toxicities are central nervous system toxicity, impairment of bone mineralization, and microcytosis [3]. Aluminum toxicity is probably the major factor in the pathogenesis of dialysis dementia, a unique neurologic complication of ESRD associated with chronic dialysis [14]. In addition, aluminum overload leads to aluminum bone disease (adynamic bone or osteomalacia) and is associated with a poor response to calcitriol therapy [15]. Musculoskeletal pain, arthralgia, and proximal muscle weakness are common
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[16]. Our data are in concordance with these observations and showed that patients with high serum aluminum levels reported more residual symptoms after parathyroidectomy. The K/DOQI guidelines suggest that a deferoxamine test should be performed when serum aluminum levels are between 60 and 200 lg/L [4]. The test is conducted by infusing 5 mg/kg of deferoxamine, an iron-chelating agent, at the end of a dialysis session. Serum aluminum levels are measured before deferoxamine infusion and 2 days later, before the next dialysis session. When the increment of serum aluminum is [50 lg/L, the test is considered positive, and deferoxamine therapy and high-efficiency dialysis should be given. Considering that parathyroidectomy may enhance aluminum deposition on the bone surface [17], our policy is not to perform parathyroidectomy in patients with a serum aluminum level above 60 lg/L. Aluminum overload may also contribute to microcytic anemia [18]. Nonetheless, there was no difference in hemoglobin levels between the low and high aluminum groups. Uremic pruritus is a common complaint of ESRD patients and can markedly affect a patient’s quality of life [19]. Pathophysiology of pruritus includes uremic alterations (particularly high calcium-phosphorus product), inflammation, opioid system, and neuropathy [20]. We noted that the high aluminum group had persistent pruritus after parathyroidectomy compared with the low aluminum group, although there was no difference between the groups in the extent of pruritus before surgery. In line with our observation, Friga et al. [21] reported that hemodialysis patients with pruritus had higher serum aluminum concentrations, and the intensity of pruritus was related to the aluminum concentration. The mechanisms of refractory pruritus after parathyroidectomy in patients with high aluminum levels are little known. The most severe cases of aluminum toxicity occur in patients who have contamination of dialysate with aluminum; however, aluminumbased binders may also play a role. Although aluminum salts are the most ‘potent’ phosphate binders, the safe dose of aluminum-based binders is yet to be determined. Several new phosphate-lowering compounds are under development [22]. Based on our results, we discourage patients from taking aluminum-containing phosphate binders. Before parathyroidectomy, patients with higher serum aluminum levels should be informed of the possibility of symptom persistence. We must acknowledge several study limitations. Bone biopsy was not performed in our patients. The evaluation and definitive diagnosis of renal osteodystrophy require a bone biopsy, which is also considered the gold standard for the diagnosis of aluminum bone disease [4]. Furthermore, long-term changes in BMD were not available in our study. Most patients were followed up at local dialysis clinic where BMD testing is infrequent. Finally, we did not
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examine longitudinal changes of serum aluminum levels. Our patients typically discontinue the use of phosphate binders after parathyroidectomy. A decrease in serial analysis of blood aluminum levels may reflect reduced ingestion of aluminum salts or enhanced bone aluminum accumulation.
Conclusion The present study demonstrated that ESRD patients with low or high serum aluminum levels had similar preoperative symptomatology and perioperative biochemical changes. However, patients with high serum aluminum levels had more residual symptoms after parathyroidectomy. Exposure to aluminum should be limited, especially among patients with refractory hyperparathyroidism who are scheduled for parathyroidectomy.
Conflict of interest The authors have no conflict of interest to declare.
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