a case of severe hungry bone syndrome following ... · right lower thyroid gland with signs of...

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For citation purposes: Anzai T, Yokoyama J, Ohba S, Ito S, Fujimaki M, Kojima M, Ikeda K. A case of severe hungry bone syndrome following parathyroidectomy analyzed with a focus on the alpha-Klotho calcium regulator. Head Neck Oncol. 2012 Sep 9;4(2):57.

Copyright © 2012 OA Publishing London

* Corresponding author Email: [email protected]

Department of Otorhinolaryngology, Juntendo University Faculty of Medicine, Tokyo, Japan

AbstractIntroductionHungry bone syndrome is a complica-tion following parathyroid surgery where the correction of primary hy-perparathyroidism is associated with unregulated bone mineralization, in-ducing severe and prolonged hypocal-caemia. The mechanisms for hungry bone syndrome are neither clear nor has a method for its prevention been established.CaseThe patient was a 29-year-old woman. She had problems with her gait due to femur pain. The serum calcium, parathyroid hormone and alkaline phosphatase levels were ele-vated. Preoperative imaging indi-cated a parathyroid tumour posterior to the right thyroid lobe. She was diagnosed with primary hyperpara-thyroidism and underwent parathy-roidectomy. Despite bisphosphonates and intensive calcium and vitamin D supplementation, the serum level of calcium remained low due to hungry bone syndrome.DiscussionWe analyzed hungry bone syndrome focusing on the discrepancy between hypocalcaemia and low-level parathy-roid hormone in terms of the alpha-Klotho calcium regulator.

IntroductionHungry bone syndrome (HBS) is a complication following parathyroid surgery where the correction of pri-mary hyperparathyroidism (PHPT) is

A case of severe hungry bone syndrome following parathyroidectomy analyzed with a focus on the

alpha-Klotho calcium regulatorT Anzai1, J Yokoyama*1, S Ohba1, S Ito1, M Fujimaki1, M Kojima1, K Ikeda1

associated with rapid bone remineral-ization, causing severe and prolonged hypocalcaemia. Following parathy-roidectomy, the parathyroid hormone (PTH) stimulus is abruptly removed. There fore, the excessive osteoclastic activity stops; however, osteoblastic activity continues, which can result in a marked increase in bone uptake of calcium to facilitate bone formation, thus predisposing the patient to symptomatic hypocalcaemia1. It has been reported that prevention of HBS can be facilitated through preopera-tive administration of bisphospho-nates, which are potent inhibitors of osteoclast activity2. However, a pri-mary cause of HBS is the low secre-tion of PTH despite hypocalcaemia. This is because the origin of HBS is a productive dysfunction of PTH after parathyroidectomy. We analyzed HBS focusing on the discrepancy between hypocalcaemia and a low-level of PTH in terms of the alpha-Klotho (a-Kl) calcium regulator. a-Kl is a new concept of PTH secretion3. Here, we report a case of severe HBS after a parathyroidectomy that occurred even after preoperative administration of bisphosphonates.

Case reportA 29-year-old woman presented to our hospital with eight-month coxalgia in November 2011. In addition, she had gait disturbance due to femur pain. The pelvic X-ray showed a lytic lesion of the right acetabular roof due to se-vere osteoporosis (Figure 1). The bone biopsy showed a brown tumour that was a bone lesion resulting from ex-cess osteoclast activity (Figure 2). A nodule was palpable on the right side of the neck. It measured 35 mm

in size and was elastic and smooth surfaced. Her laboratory findings are summarized in Table 1. Elevated se-rum total and ionized calcium levels, together with an increased intact PTH level, confirmed the diagnosis of PHPT. An ultrasonographic imaging of the neck indicated a round hy-poechogenic mass. There was a well-defined margin separate from the right lower thyroid gland with signs of increased blood flow. A computed tomography (CT) of the neck indi-cated a mass inferior to the right lobe (Figure 3). A subtraction scintigraphy with 99mTc-MIBI indicated a parathy-roid tumour at the right lobe of the thyroid gland (Figure 4). Thus, we di-agnosed PHPT of the skeletal type caused by a large parathyroid ade-noma. The screening tests for pitu-itary, adrenal and pancreatic tumours were negative for multiple endocrine neoplasia (MEN). Bone mineral mea-surements were also performed be-fore the operation by dual-energy X-ray absorptiometry (DXA). The pre-operative bone mineral density at the lumbar spine (L2–L4) was 0.689 g/cm2. The Z value and the T score, which is a bone-marrow derived (BMD) index

Figure 1: The pelvic X-ray shows a lytic lesion of the right acetabular roof because of severe osteoporosis.



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surgery, a single large parathyroid tumour was removed. No other para-thyroid lesions were detected. The tumour was pathologically deter-mined to be parathyroid adenoma. Two days following the operation, the patient complained of tetany and the preoperative serum calcium level of 13.3 mg/dL was reduced promptly to 7.7 mg/dL. Despite intravenous and oral calcium supplementation and vitamin D supplementation, the serum level of calcium remained low due to HBS after the operation. Irrespective of the persistent hypo-calcaemia, the serum intact PTH level could not be elevated. Urinary calcium excretion was consis-tently < 0.5 g/day. The serum alkaline phosphatase (ALP) activity of skele-tal isozyme temporarily increased to > 3500 IU/L. The patient was dis-charged 14 days after her operation since she did not show any particular symptoms. A laboratory study performed 14 days after the opera-tion showed a serum calcium level of 7.6 mg/dL and a phosphorous level of 2.8 mg/dL. This was only be-cause of oral calcium and vitamin D

Figure 2: Pathological findings of the bone. (Left: low-power magnification, right: high-power magnification). Pathological findings indicated that there were many osteoclasts in the bone and the bone lesion was consistent with a brown tumour arising from hyperparathyroidism.

200 mm

Table 1 Laboratory dataHaematological studies Endocrinological studies

Leucocyte 6700/mm3 Intact parathyroid hormone 1860 pg/mL Erythrocyte 432 × 104/mm3 Calcitonin 28 pg/mL

Haemoglobin 12.6 g/dL Free T4 0.6 ng/dL Platelet 24.1 × 104/mm3 Free T3 3.3 pg/mL

Blood chemistry Thyroid-stimulating hormone 3.7 μU/mL Albumin 4.3 g/dL Luteinizing hormone 6.7 mIU/mL Alkaline phosphatase 4762 IU/L Follicle stimulating hormone 4.9 mIU/mL Fasting blood glucose 88 mg/dL Growth hormone 2.1 ng/mL Calcium 15 mg/dL Prolactin 22.5 ng/mL Inorganic phosphate 2.5 mg/dL Adrenocorticotropic hormone 15.9 pg/mL 1,25-(OH)2 Vit. D 103 pg/mL Immunoreactive insuline 4.6 μU/mL HbA1c 4.6% C-peptide reactivity 0.8 ng/mL

Urinary excretion Gastrin 37 pg/mL Calcium 9.7 mg/dL NTx/creatinine 784.5 nmol BCE/mmol Cr Phosphate 43.4 mg/dL

normalized to age-, sex- and ethnicity-matched controls, was 68% and -2.9 SD preoperatively.

The patient received bisphos-phonate for hypercalcaemia (first zoledronate 4 mg/day for two days,

followed by oral alendronate 15 mg/day) and elcitonin (40 unit/day) treatment until the operation. The serum calcium level of 15 mg/dL decreased to 13.3 mg/dL. Then she underwent parathyroidectomy. At

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Case report

that the preoperative calcium con-centration was not related to the occurrence of hypocalcaemia2,6. Some researchers recommend the administration of bisphosphonate to prevent HBS in patients with PHPT2,7. Bisphos phonate has a potent effect on the inhibition of osteoclastic bone resorption and is widely used in the treatment of osteoporosis and hy-percalcaemia8–10. In the present case, despite bisphosphonate supplemen-tation before the operation and intensive calcium and vitamin D sup-plementation after the operation, the serum level of calcium remained low. Currently, the methods for prevent-ing HBS remain controversial.

Recently, a new calcium homeosta-sis regulator was discovered and named a-Kl3,11. a-Kl is a unique mol-ecule that plays pivotal roles in the rapid tuning of the extracellular Ca2+ concentration through transepithelial Ca2+ transport and PTH secretion. This results in a subsequent Ca2+ increase in the serum. Through these path-ways, a-Kl participates in the regula-tion of calcium homeostasis of the cerebrospinal fluid (CSF) and blood/body fluids by its actions in the cho-roid plexus, parathyroid glands and distal convoluted tubule (DCT) neph-rons. In this respect, a-Kl is a key player that integrates ‘a multi-step regulatory system of calcium homeostasis’ that rapidly adjusts the extracellular cal-cium concentration and continuously maintains its concentration within a narrow physiological range11.

We focused the discrepancy be-tween hypocalcaemia and the low-level of PTH in the present case of HBS. According to the central theory of serum Ca concentration, hypocal-caemia stimulates the secretion of PTH and the serum calcium level is rapidly elevated. However, in our pa-tients, the serum PTH level remained low two weeks following the opera-tion despite hypocalcaemia. With respect to this incomprehensible problem, we referred to Björklund’s report, which noted that a-Kl mRNA

parathyroid adenoma and old age1. Our patient’s laboratory findings in-cluded high levels of intact PTH, se-rum calcium and ALP. In addition, the patient had a large parathyroid ade-noma and severe osteoporosis. She was categorized as a high-risk pa-tient for HBS.

The prevention of HBS has not yet been established. Smith et al have rec-ommended that preoperative treat-ment with calcitriol for 5–10 days may prevent HBS in the post-parathyroid-ectomy state4,5. However, Mittendorf et al and I-Te Lee et al have reported

supplementation. After five months, her serum level of calcium and ALP became normalized.

DiscussionHBS is a postoperative complication of PHPT due to unregulated bone min-eralization. It results in severe and prolonged hypocalcaemia. Braiser and Nussbaum followed 198 patients after operation for PHPT. They found that the risk factors for the develop-ment of HBS included high preopera-tive levels of serum calcium, PTH, ALP, blood urea nitrogen (BUN), large

Figure 3: Computed tomography of the neck. A well-enhanced mass was infe-rior to the right lobe with no invasion to the neighbouring organs.

ANT99mTc-MIBI

20 min

ANT99mTc-MIBI

20 hr

Figure 4: MIBI scan. Left: 20-minute delayed image. Right: 2-hour delayed image. These images of technetium-99m-MIBI are consistent with right-sided parathyroid adenoma.



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to prevent HBS may be effective in re-leasing suppressed a-Kl in hypercal-caemia.

A significant risk factor of HBS may be not the high calcium concentration, but the duration of the normalized calcium concentration. Accordingly, a-Kl can be restored and can secrete PTH whenever calcium is decreased.

Serum soluble a-Kl can be measured by the ELISA method13. Therefore, measurement of serum soluble a-Kl may predict potential cases of HBS immediately after parathyroidectomy.

Further examinations for HBS and a-Kl are required in the future.

Thus, it is imperative to carefully check for serum calcium and symp-toms following an operation. This is especially important when treating high-risk HBS patients.

Abbreviations listALP, alkaline phosphatase; a-Kl, alpha-Klotho; BUN, blood urea nitrogen; CSF, cerebrospinal fluid; CT, computed tomography; DCT, distal convoluted tubule; HBS, hungry bone syndrome; PHPT, primary hyperparathyroidism; PTH, parathyroid hormone.

ConsentWritten informed consent was ob-tained from the patient for publication of this case report and any accompa-nying images.

AcknowledgementThis study was supported in part by Grants-in-Aid for Scientific Research from the Ministry of Education, Cul-ture, Sports, Science and Technology (MEXT) (22591920) of Japan.

References1. Brasier AR, Nussbaum SR. Hungry bone syndrome: clinical and biochemical pre-dictors of its occurrence after parathy-roid surgery. Am J Med. 1998 Apr;84(4): 654–60.2. Lee IT, Sheu WH, Tu ST, Kuo SW, Pei D. Bisphosphonate pretreatment at-tenuates hungry bone syndrome post-operatively in subjects with primary

and protein expressions were de-creased or undetectable in parathy-roid adenomas from PHPT patients, and that parathyroid a-Kl expression in PHPT was closely correlated to the serum calcium levels. As a result, serum calcium is strongly associated with parathyroid a-Kl expression in PHPT12. We considered that the postoperative hypocalcaemia in the

present case resulted from the long-term suppression of a-Kl by the para-thyroid adenomas. As a result, a-Kl could not increase the PTH and Ca concentration in response to the de-creasing calcium level due to unregu-lated bone remineralization (Figure 5). This is potentially the primary problem of HBS. In terms of a-Kl, preoperative ad ministration of bisphosphonates

Figure 5: Changes in Ca, PTH and ALP. (a) Changes in Ca and PTH. (b) Changes in PTH and ALP.

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independent of parathyroid glandular so-dium/potassium-ATPase activity. Kidney Int. 2011 Apr;79(7):742–8. Epub 2011 Jan 5.12. Björklund P, Krajisnik T, Akerström G, Westin G, Larsson TE. Type I membrane klotho expression is decreased and in-versely correlated to serum calcium in primary hyperparathyroidism. J Clin Endocrinol Metab. 2008 Oct;93(10): 4152–7. 13. Amazaki Y, Imura A, Urakawa I, Shimada T, Murakami J, Aono Y, et al. Establishment of sandwich ELISA for soluble alpha-Klotho measurement: Age-dependent change of soluble alpha-Klotho levels in healthy subjects. Biochem Biophys Res Commun. 2010 Jul;398(3): 513–8.

7. Kumar A, Ralston SH. Bisphospho nates prevent the hungry bone syndrome. Nephron. 1996 Aug;74(4):729.8. Khan AA, Bilezikian JP, Kung AW, Ahmed MM, Dubois SJ, Ho AY, et al. Alendronate in primary hyperparathy-roidism: a double-blind, randomized, placebo-controlled trial. J Clin Endocrinol Metab. 2004 Jul;89(7):3319–25.9. Fleisch H. Bisphosphonates: mecha-nisms of action. Endocr Rev. 1998 Feb; 19(1):80–100.10. Rodan GA. Bisphosphonates and pri-mary hyperparathyroidism. J Bone Miner Res. 2002 Nov;17 Suppl 2:N150–3.11. Martuseviciene G, Hofman-Bang J, Clausen T, Olgaard K, Lewin E. The secretory response of parathyroid hor-mone to acute hypocalcemia in vivo is

hyperparathyroidism. J Bone Miner Metab. 2006 May;24(3):255–8.3. Imura A, Tsuji Y, Murata M, Maeda R, Kubota K, Iwano A, et al. alpha-Klotho as a regulator of calcium ho meostasis. Science. 2007 Jun;316(5831):1615–8.4. Smith D, Murraf BF, McDermott E, O’Shea D, McKenna MJ, McKenna TJ. Hungry bones without hypocalcaemia following parathyroidectomy. J Bone Miner Metab. 2005 Nov;23(6):514–5.5. Llach F. Parathyroidectomy in chronic renal failure: indication, surgical approach and the use of calcitriol. Kidney Int Suppl. 1990 Sep;29:S62–8.6. Mittendorf EA, Merlino JI, McHenry CR. Post-parathyroidectomy hypocalcemia: incidence, risk factors, and management. Am Surg. 2004 Feb;70(2):114–20.

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