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Calcium Homeostasis in Patients with Graves' Disease
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery. Centrum för klinisk forskning dalarna.
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Patients with Graves´ Disease (GD) have a higher risk of developing more severe and prolonged hypocalcaemia after total thyroidectomy (TT) than patients who undergo surgery for benign atoxic goitre. Since TT is the most effective treatment for GD, it is crucial to identify mechanisms for postoperative hypocalcaemia. The aim of this thesis was to study the mechanisms of calcium metabolism in patients with GD.

It is safe to operate on GD patients with TT. Results in Paper I showed fewer recurrences and equal complication rates compared to patients who underwent subtotal thyroidectomy (ST). The transient lowering of PTH seen in the hypocalcaemic patients was fully restored one month after surgery (Papers II and V).

The calcium-sensing receptor (CaSR) is crucial for maintaining plasma calcium, and single nucleotide polymorphisms (SNPs) in the gene may alter the sensing function. Thus, we analysed SNPs in CaSR in GD patients (Paper II) and showed that they had a more left-shifted calcium-PTH set-point compared to controls, implicating higher sensitivity. This is also supported by the results in the group of postoperatively hypocalcaemic patients. They already had lower plasma calcium preoperatively (Papers II, IV and V) and lacked the T/G G/A G/C, a haplotype shown in Paper III to have a close relationship to higher p-calcium levels. Moreover, a lack of the T allele in rs1801725 was seen in the group of patients needing permanent treatment with calcium and vitamin D, i.e. > 12 months, (paper V).

Patients who became hypocalcaemic (p-calcium < 2.00 mmol/L) on day one postoperatively, had lower preoperative levels of thyroid stimulating hormone (TSH) and higher levels of  T3, this was also applied to the patient groups requiring temporary or permanent postoperative treatment (Papers II and V). In addition, hypocalcaemic patients treated for less than six months with anti-thyroid drugs had higher levels of bone metabolism markers CTX and P1NP than normocalcaemic patients (Paper V).

In conclusion, the postoperative period of hypocalcaemia seen in patients with GD is a complex medical condition, caused by a combination of surgical trauma, different SNPs in CaSR, and high bone metabolism related to preoperative thyroid metabolism.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2016. , 51 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1212
Keyword [en]
Graves' Disease, Calcium homeostasis, Total thyroidectomy, Bone metabolism, Calcium sensing receptor
National Category
Clinical Medicine
Research subject
Surgery
Identifiers
URN: urn:nbn:se:uu:diva-283075ISBN: 978-91-554-9552-7 (print)OAI: oai:DiVA.org:uu-283075DiVA: diva2:918150
Public defence
2016-06-02, Föreläsningssalen Falu Lasarett, Söderbaums väg 8, entré I, Falun, 10:00 (Swedish)
Opponent
Supervisors
Available from: 2016-05-12 Created: 2016-04-10 Last updated: 2016-06-01
List of papers
1. Management of Grave's Disease Is Improved by Total Thyroidectomy
Open this publication in new window or tab >>Management of Grave's Disease Is Improved by Total Thyroidectomy
2012 (English)In: World Journal of Surgery, ISSN 0364-2313, E-ISSN 1432-2323, Vol. 36, no 8, 1943-1946 p.Article in journal (Refereed) Published
Abstract [en]

A retrospective analysis was performed on 267 consecutive patients with Graves' disease (GD). The principal aim of this study was to evaluate the risk for recurrence and complications when changing the surgical method from subtotal (ST) to total thyroidectomy (TT). Information from 267 consecutive patients operated on for GD between 2000 and 2006 was collected at Uppsala University Hospital (143) and Falun County Hospital (128). There were 229 women and 38 men. Four patients were operated on twice. A total of 40 STs and 229 TTs were performed. Results were compared to those of a previous cohort from the same hospital, with a majority of STs (157/176) performed from 1980 to 1992. The risk for relapse of GD was reduced from 20 to 3.3 % after the shift from ST to TT. In terms of surgical complications, 2.2 % demonstrated permanent vocal cord paralysis and 4.5 % had persistent hypocalcemia, not significant when compared to the previous cohort. In spite of TT, there were four recurrences, all due to remnant thyroid tissue high up at the hyoid bone. Changing the surgical method did not affect postoperative progression of dysthyroid ophthalmopathy (DO, 7.0 vs. 7.5 %). There were no differences in outcome with respect to which hospital the patients had their operation. Change from ST to TT dramatically reduced the risk for recurrence of GD without increasing the rate of complications. TT is not more effective than ST in hampering progression of DO as has been advocated by some. Careful surgical dissection up to the hyoid bone is necessary to avoid recurrence.

National Category
Surgery
Identifiers
urn:nbn:se:uu:diva-178078 (URN)10.1007/s00268-012-1617-x (DOI)000305988400029 ()
Available from: 2012-07-30 Created: 2012-07-27 Last updated: 2017-12-07Bibliographically approved
2. Left-shifted relation between calcium and parathyroid hormone in Graves' Disease
Open this publication in new window or tab >>Left-shifted relation between calcium and parathyroid hormone in Graves' Disease
2014 (English)In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 99, no 2, 545-551 p.Article in journal (Refereed) Published
Abstract [en]

Background:

Patients with Graves' disease (GD) have disturbances in calcium regulation with manifestations such as postoperative hypocalcemia. We have investigated the thyroid as well as the parathyroid function in detail.

Material and Method:

A series of patients undergoing total thyroidectomy for GD (n=56) or Multi Nodular Goitre (MNG, n=50) were scrutinized for postoperative hypocalcemia, need for calcium and/or vitamin D substitution. CiCa-clamp was used in 14 patients and 21 controls to quantify the secretion of PTH in relation to the ionized plasma calcium level. The setpoint, equal to the plasma ionized calcium concentration at which 50% of the maximal secretion of PTH is inhibited, as well as other CiCa-related parameters were calculated.

Results:

Hypocalcemia was present in 48% of GD and 41.2% of patients with MNG postoperatively. Patients with GD had lower calcium levels, 18% had S-Ca< 2.00 mmol/L compared to 4.0% in the MNG group, p=0.02. A higher degree of GD patients were given parenteral calcium-substitution during the hospital stay (3.6% vs 0 %) and oral calcium substitution at discharge (48% vs 10%), although they had normal vitamin D3 levels. The GD group showed a significantly left-shifted setpoint compared to the normal group on CiCa clamp, 1.16 mmol/l vs. 1.20 mmol/L (p<0.001), as well as an increased PTH release to hypocalcemic stimulus. GD patients also show an association between degree of subclinical toxicosis at time of surgery and risk for developing postoperative hypocalcemia.

Conclusion:

Patients with GD demonstrate dysregulation of the calcium homeostasis by several parameters. GD patients have lower postoperative S-calcium compared to patients with MNG, lower calcium/PTH setpoint and a significantly increased release of PTH to hypocalcemic stimulus compared to controls. The CiCa clamp response in GD patients with normal 25-OH-vitamin D3 levels mimics that of obese patients in which vitamin D insufficiency has been proposed as an underlying cause.

National Category
Surgery
Identifiers
urn:nbn:se:uu:diva-212144 (URN)10.1210/jc.2013-2500 (DOI)000333460300053 ()24248181 (PubMedID)
Available from: 2013-12-06 Created: 2013-12-06 Last updated: 2017-12-06Bibliographically approved
3. Association between Calcium Sensing Receptor Polymorphisms and Plasma Calcium and Parathyroid hormone in a Swedish well characterized Cohort
Open this publication in new window or tab >>Association between Calcium Sensing Receptor Polymorphisms and Plasma Calcium and Parathyroid hormone in a Swedish well characterized Cohort
Show others...
(English)Article, review/survey (Other academic) Submitted
Keyword
Calcium sensing receptor, PIVUS, Calcium, Parathyroid hormone
National Category
Clinical Medicine
Research subject
Medical Science
Identifiers
urn:nbn:se:uu:diva-282594 (URN)
Available from: 2016-04-10 Created: 2016-04-05 Last updated: 2017-03-23Bibliographically approved
4. Calcium Sensing Receptor Polymorphisms and their realtionships to postoperative hypocalcaemia in Graves´disease
Open this publication in new window or tab >>Calcium Sensing Receptor Polymorphisms and their realtionships to postoperative hypocalcaemia in Graves´disease
Show others...
(English)Manuscript (preprint) (Other academic)
Keyword
Graves' Disease, Calcium sensing receptor, Hypocalcemi, Total thyroidectomy
National Category
Medical and Health Sciences
Research subject
Medical Science
Identifiers
urn:nbn:se:uu:diva-282596 (URN)
Available from: 2016-04-10 Created: 2016-04-05 Last updated: 2016-06-01
5. Biochemical Markers in Bone Metabolism in Patients with Graves' Disease
Open this publication in new window or tab >>Biochemical Markers in Bone Metabolism in Patients with Graves' Disease
(English)Manuscript (preprint) (Other academic)
Keyword
Graves' Disease, Bone metabolism, Calcium sensing receptor, Hypocalcaemia, Total thyroidectomy
National Category
Clinical Medicine
Research subject
Medical Science
Identifiers
urn:nbn:se:uu:diva-282595 (URN)
Available from: 2016-04-10 Created: 2016-04-05 Last updated: 2016-06-01

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