Katja Schlosser

Surgical treatment of tertiary hyperparathyroidism : The choice of procedure matters!

BackgroundParathyroid surgery (PTX) in patients with tertiary hyperparathyroidism (tHPT) may endanger the long-term survival of transplanted renal grafts. The mechanism by which graft function deteriorates is unknown. We reviewed our experience in regard to the operative procedures and postoperative outcome.MethodsSixty-nine patients were operated on for tHPT between 1987 and 2006 at our institution. Serum (s) calcium, s-creatinine, and levels of intact parathyroid hormone (PTH) were measured before and after PTX. The Modification of Diet in Renal Disease (MDRD) equation was used to estimate glomerular filtration rate (GFR).ResultsThe entire patient group developed a deterioration of kidney graft function after PTX. Nineteen of 69 patients developed a decrease in GFR of more than 20% during the hospital stay, persisting for more than one year after PTX. Ten of them had to restart dialysis during the first year after PTX. Mean preoperative s-creatinine was 4.4 ± 0.6 mg/dl in these patients. When divided according to the surgical procedure performed, only the subgroup who underwent total parathyroidectomy showed a significant worsening of graft function when compared to subtotal or reoperative PTX.ConclusionsPTX is an efficient way to treat tHPT but represents a risk for impairing graft function, especially for patients that already demonstrate poor kidney function at the time of surgery. In the aim to prevent transient hypoparathyroidism, which may provoke reduced graft perfusion, as one possible cause of kidney graft deterioration associated with PTX, one should consider subtotal instead of total parathyroidectomy.

Comparison of total parathyroidectomy without autotransplantation and without thymectomy versus total parathyroidectomy with autotransplantation and with thymectomy for secondary hyperparathyroidism: TOPAR PILOT-Trial

BackgroundSecondary hyperparathyroidism (sHPT) is common in patients with chronic renal failure. Despite the initiation of new therapeutic agents, several patients will require parathyroidectomy (PTX). Total PTX with autotransplantation of parathyroid tissue (TPTX+AT) and subtotal parathyroidectomy (SPTX) are currently considered as standard surgical procedures in the treatment of sHPT. Recurrencerates after TPTX+AT or SPTX are between 10% and 12% (median follow up: 36 months).Recent retrospective studies demonstrated a lower rate of recurrent sHPT of 0–4% after PTX without autotransplantation and thymectomy (TPTX) with no higher morbidity when compared to the standard procedures. The observed superiority of TPTX is flawed due to different definitions of outcomes, varying follow up periods and different surgical treatment strategies (with and without thymectomy).Methods/DesignPatients with sHPT (intact parathyroid hormone > 10 times above the upper limit of normal) on long term dialysis (>12 months) will be randomized either to TPTX or TPTX+AT and followed for 36 months. Outcome parameters are recurrence rates of sHPT, frequencies of reoperations due to refractory hypoparathyroidism or recurrent/persistent hyperparathyroidism, postoperative morbidity and mortality and quality of life. 50 patients per group will be randomized in order to obtain relevant frequencies of outcome parameters that will form the basis for a large scale confirmatory multicentred randomized controlled trial.DiscussionsHPT is a disease with a high incidence in patients with chronic renal failure. Even a small difference in outcomes will be of clinical relevance. To assess sufficient data about the rate of recurrent sHPT after both methods, a multicentred, randomized controlled trial (MRCT) under standardized conditions is mandatory.Due to the existing uncertainties the calculated number of patients necessary in each treatment arm (n > 4000) makes it impossible to perform this study as a confirmatory trial. Therefore estimates of different outcomes are performed using a pilot MRCT comparing 50 versus 50 randomized patients in order to establish a hypothesis that can be tested thereafter.If TPTX proves to have a lower rate of recurrent sHPT, no relevant disadvantages and no higher morbidity than TPTX+AT, current surgical practice may be changed.Trial registrationInternational Standard Randomized Controlled Trial Number Registration (ISRCTN86202793)

Unique expression pattern of the EMT markers Snail, Twist and E-cadherin in benign and malignant parathyroid neoplasia

BACKGROUND Epithelial and mesenchymal transitions (EMT) are essential for embryonic development and progression of non-invasive tumor cells into malignant, metastatic carcinomas. During embryogenesis, the parathyroid glands develop from pharyngeal pouches and migrate to their final destinations, densely enclosed by mesenchymal neural crest cells. In this study, we examined the expression of the EMT markers Snail, Twist and E-cadherin in normal parathyroid glands and benign and malignant parathyroid diseases. METHODS Using immunohistochemistry, we compared expression of E-cadherin, Snail and Twist in 25 patients with parathyroid adenoma, 25 patients with parathyroid hyperplasia, and nine patients with parathyroid cancer with normal parathyroid glands. RESULTS Normal parathyroid glands, parathyroid adenomas, and parathyroid hyperplasias showed a typical membranous E-cadherin staining pattern. Expression of Snail was found in 22/25 parathyroid adenomas and in all parathyroid hyperplasias. Twist was expressed in 22/25 of parathyroid adenomas and in 20/25 parathyroid hyperplasias. Snail and Twist positive cells were homogeneously distributed throughout the gland. However, in all nine parathyroid carcinomas, membranous E-cadherin staining was lost. In addition, the expression pattern of Snail and Twist was changed and mostly limited to the invasive front of cancer tissue samples. CONCLUSION Expression of Snail and Twist at the invasive front and consecutive loss of E-cadherin in parathyroid carcinomas suggests a key role of EMT in the tumorigenesis of this cancer. The unique expression pattern could help to distinguish between an adenoma and a non-metastatic carcinoma. Loss of E-cadherin and change of the expression pattern of Snail and Twist together should result in an en bloc resection or a close follow-up.

Medical and Surgical Treatment for Secondary and Tertiary Hyperparathyroidism

Prevention and treatment of secondary hyperparathyroidism (SHPT) in patients on chronic maintenance hemodialysis and of tertiary hyperparathyroidism (THPT) in patients after kidney transplantation is a challenge for the nephrologist and for the surgeon. Indication and results of medical and surgical therapy for SHPT and THPT have remained under discussion during the last decades. This review resumes the current medical and surgical strategies for patients with SHPT and THPT.

An economic comparison of surgical and medical therapy in patients with secondary hyperparathyroidism—the German perspective

BACKGROUND Treatment options for secondary hyperparathyroidism were significantly amended with the introduction of cinacalcet and paricalcitol. Limitations of resources in public health systems demand detailed analyses of accruing costs. The aim of this study was to compare the costs of these new treatment modalities to surgery. METHODS Patients who underwent initial parathyroidectomy (n = 91) and patients treated with cinacalcet or paricalcitol (n = 100) at an ambulatory dialysis center between 01/2003 and 12/2006 were analyzed. The revenues of both therapies for the funding agencies were calculated by a cost-cost analysis. The real arising costs of the supplier were analyzed and compared to the revenues. RESULTS Treatment costs for cinacalcet (60 mg/day/year) were 5828.40€ and 4485.20€ for paricalcitol (15 μg/week/year). Revenues for inpatient surgical treatment according to the German DRG system were 3755.38€/case. Additionally, costs for postoperative ambulatory therapies were 545.05€ for the first year and 384.97€ for the following. CONCLUSION Due to linearly increases, expenses of medical treatment with cinacalcet for more than 9 months or paricalcitol for more than 12 months exceeded the costs of surgical therapy. The indication of these new medical therapies should be restricted to patients as an interim solution ahead of surgery or in patients considered unfit for surgery.

Frequency of Ectopic and Supernumerary Intrathymic Parathyroid Glands in Patients with Renal Hyperparathyroidism: Analysis of 461 Patients Undergoing Initial Parathyroidectomy with Bilateral Cervical Thymectomy

BackgroundThe frequency of intrathymic parathyroid glands (IPGs) in patients undergoing parathyroidectomy for renal hyperparathyroidism (rHPT) varies considerably between 14.8% and 45.3%. Total parathyroidectomy with autotransplantation and subtotal parathyroidectomy are the most accepted surgical procedures to treat patients with rHPT. However, routine bilateral cervical thymectomy (BCT) is still discussed, although controversially.MethodsFrom a prospective database of patients who underwent parathyroid surgery for rHPT between 1975 and 2009, patients with routine BCT at initial PTX were further analyzed regarding the frequency of ectopic and supernumerary IPGs. Duration of hemodialysis and stage of chronic kidney disease were correlated with the frequency of supernumerary IPGs to elucidate a potential role of long-standing proliferation stimuli to any surplus parathyroid tissue.ResultsInitial parathyroidectomy with BCT was performed in 461 patients. IPGs were resected in 205 of them (44.5%). They were ectopic in 181 (39.3%) and supernumerary in 30 patients (6.5%). The frequency of supernumerary IPGs in patients on permanent hemodialysis was 7.4% (29/392), 3.9% (1/26) in predialysis patients, and 0% (0/43) in patients after successful kidney transplantation. This differences reached no statistical significance.ConclusionsBCT is essential in patients with fewer than four parathyroid glands identified at typical positions. Because of the low frequency of supernumerary IPGs and a suspected low proliferation stimulus, the relevance of BCT after resection of four glands in predialysis patients and those after successful kidney transplantation must be questioned. Nevertheless, routine BCT seems to be acceptable and can be recommended in patients on permanent hemodialysis not awaiting kidney transplantation until proven otherwise by prospective trials.

Assessing the Site of Recurrence in Patients with Secondary Hyperparathyroidism by a Simplified Casanova Autograftectomy Test

Patients with recurrent secondary hyperparathyroidism (rSHPT) following total parathyroidectomy and autotransplantation were prospectively studied by a modified Casanova test to discriminate between the graft-bearing arm and the neck as the site of the recurrence. The test measures intact parathyroid hormone (PTH) in blood obtained from the non-graft-bearing arm before an ischemic period and from the arm bearing the parathyroid graft during an ischemic period caused by an Esmarch bandage. The aim of this study was to evaluate the time course of PTH levels during the test and to establish an abbreviated procedure. A series of 30 patients with rSHPT who were admitted for reoperative surgery between 1994 and 2002 were studied. Systemic PTH levels were determined prior to suprasystolic exclusion of the graft-bearing arm as well as 2, 4, 6, 8, 10, 20, and 30 minutes during it and at 10 minutes afterward. Results were interpreted with a simple algorithm that suggested graft-dependent recurrence (GDR) whenever PTH levels dropped by more than 50% and neck-dominated recurrence (NDR) whenever the PTH levels dropped to less than 20%. Patients were operated on accordingly. Biochemical normalization of calcium and PTH was defined as success. Altogether, 15 patients had GDR and were cured after graft explantation. All of these patients were identified within 4 minutes of starting the test. Another 12 patients had NDR and were cured by excising overlooked or supernumerary glands. PTH levels were indeterminate in three patients (10%). Clinically, NDR is likely in all of these cases, but the test results were firmly established with 100% accuracy 8 minutes after the start of the test procedure. This abbreviated form of the Casanova test is advantageous for accurately determining the site of recurrence in the presence of rSHPT. It is less time-consuming, satisfactory in an ambulatory setting, equally effective, and less invasive than the original Casanova procedure.

Long-term control of parathyroid hormone and calcium-phosphate metabolism after parathyroidectomy in children with chronic kidney disease

BACKGROUND Hyperparathyroidism (HPT) is an essential contributor to bone disease and cardiovascular calcifications in children with chronic kidney disease (CKD). Pharmacological and dietary interventions are of limited efficacy; calcimimetics are not yet recommended in children. Parathyroidectomy (PTX) is ultimately performed if HPT becomes refractory to conservative measures; the long-term results and the impact of subsequent kidney transplantation (NTX), however, have not yet been evaluated. METHODS We analyzed the postsurgical course of 18 paediatric CKD patients with refractory HPT who underwent PTX and autotransplantation of tissue fragments. PTX was successful in all but one patient with an ectopic fifth gland; median follow-up time was 8.3 (range 2.8-19) years. RESULTS Parathyroid hormone (PTH) dropped within 1 year after PTX from 1030 +/- 108 to 98 +/- 18 pg/ml, Ca*P from 59.5 +/- 3 to 49 +/- 2 mg(2)/dl(2). Oral calcium supply transiently increased from 18.7 +/- 4.2 to 24.1 +/- 4.8 mg/kg/day within the first 6 months (all P < 0.05). Haemoglobin increased from 10.7 +/- 0.4 to 11.5 +/- 0.3 g/dl (P < 0.01), despite similar erythropoietin dose and ferritin levels. In patients on long-term dialysis, Ca*P increased again after 18 months; three patients required a second PTX after 3.8, 12 and 12.3 years. Twelve patients underwent NTX 1.8 (0.3-3.8) years after PTX, which decreased mean PTH and Ca*P into the target range throughout the entire post-NTX observation period. Postoperative complications included one transient recurrent nerve palsy, one hypocalcaemic seizure and a case of haemopericardium. At present, no patient has clinical signs of bone disease. CONCLUSIONS PTX accomplishes long-term control of HPT and calcium-phosphate metabolism in children with CKD and following PTX and may thus mitigate uraemic bone and cardiovascular disease. This has to be taken into account if alternative long-term therapy with calcimimetics (with as yet unknown effects on longitudinal growth and pubertal development) is considered.

Differentiation between Thyroidal and Ectopic Calcitonin Secretion in patients with Coincidental Thyroid Nodules and Pancreatic Tumors - A Report of Two Cases

Although elevated blood levels of calcitonin are considered highly indicative for the presence of medullary thyroid carcinomas, they may be observed in patients with chronic kidney disease or in consequence of ectopic calcitonin production. We report two patients who presented with excessively elevated calcitonin levels. Diagnostic work-up revealed a single thyroid nodule and a pancreatic tumor with ectopic calcitonin secretion in both of them. On the basis of these case reports, the diagnostic work flow and management in case of clearly elevated calcitonin levels are described and discussed.

Total Parathyroidectomy With Routine Thymectomy and Autotransplantation Versus Total Parathyroidectomy Alone for Secondary Hyperparathyroidism: Results of a Nonconfirmatory Multicenter Prospective Randomized Controlled Pilot Trial.

Objective: This randomized controlled multicenter pilot trial was conducted to find robust estimates for the rates of recurrence of 2 surgical strategies for secondary hyperparathyroidism (SHPT) within 36 months of follow-up. Background: SHPT is a frequent consequence of chronic renal failure. Total parathyroidectomy with autotransplantation (TPTX+AT) and subtotal parathyroidectomy (SPTX) are the standard surgical procedures. Total parathyroidectomy alone (TPTX) might be a good alternative, as morbidity and recurrence rates are low according to small-scale retrospective studies. Methods: The trial was performed as a nonconfirmatory randomized controlled pilot trial with 100 patients on long-term dialysis with otherwise uncontrollable SHPT to generate data on the rate of recurrent disease within a 3-year follow-up period after TPTX or TPTX+AT. Parathyroid hormone (PTH) and calcium levels, recurrent or persistent hyperparathyroidism, parathyroid reoperations, morbidity, and mortality were evaluated during a 3-year follow-up. Results: A total of 52 patients underwent TPTX and 48 TPTX+AT. Patient characteristics, preoperative baseline data, duration of surgery (02:29 vs 02:47 hrs, P = 0.17) and mean hospital stay (10 ± 7.1 vs 8 ± 3.7 days, P = 0.11) did not differ significantly. Persistent SHPT developed in 1 TPTX and 2 TPTX+AT patients. None of the TPTX patients required delayed parathyroid AT to treat permanent hypoparathyroidism. Serum-calcium values were similar (2.1 ± 0.3 vs 2.1 ± 0.2, P = 0.95) whereas PTH rose by time in the TPTX+AT group and was significantly higher at the end of follow-up when compared with the TPTX group (31.7 ± 43.6 vs 98.2 ± 156.8, P = 0.02). Recurrent SHPT developed in 4 TPTX+AT and none of the TPTX patients. Conclusions: TPTX+AT and TPTX seem to be safe and equally effective for the treatment of otherwise uncontrollable SHPT. TPTX seems to suppress PTH more effectively and showed no recurrences after 3 years. The hypothesis that TPTX is superior to TPTX+AT referring to the rate of recurrent SHPT has to be tested in a large-scale confirmatory trial. Nevertheless, TPTX seems to be a feasible alternative therapeutic option for the surgical treatment of SHPT.