Hypercalcemia upon denosumab withdrawal in primary hyperparathyroidism: a case report and literature review.

Denosumab discontinuation is associated with a rapid increase in bone resorption and a decrease in bone mineral density. Spontaneous vertebral fractures may occur as a side effect of the rebound of bone resorption. Cases of rebound-linked hypercalcemia have also been described, moderate in women with osteoporosis and breast cancer and severe in children receiving oncological doses of denosumab. We report the case of an adult woman with primary hyperparathyroidism and moderate hypercalcemia, treated with denosumab for osteoporosis, who developed severe hypercalcemia and spontaneous vertebral fractures (SVFs) after denosumab discontinuation. An 86-year-old woman with densitometric osteoporosis was treated for 3 years with 60 mg of subcutaneous denosumab every 6 months. She was known to have primary hyperparathyroidism, with a serum albumin-corrected calcium of 2.82 mmol/l (NV 2.15-2.5) at the end of denosumab effect. Nine months after the last denosumab injection, she was hospitalized due to worsening overall health. Clinical evaluation revealed severe hypercalcemia (calcium 3.35 mmol/l). Very high values of bone turnover markers (BTMs) suggested a rebound effect due to denosumab discontinuation. An X-ray showed multiple new SVFs. After injection of denosumab 60 mg, serum calcium rapidly decreased and BTMs were dramatically reduced. A surgical approach by minimally invasive parathyroidectomy allowed for definite resolution of hyperparathyroidism and hypercalcemia. This case suggests that hypercalcemia can be a side consequence of denosumab discontinuation, which can become severe when other causes of hypercalcemia, such as primary hyperparathyroidism, are present.

Lithium-Associated Hypercalcemia: Pathophysiology, Prevalence, Management.

BACKGROUND: Lithium-associated hypercalcemia (LAH) is an ill-defined endocrinopathy. The aim of the present study was to determine the prevalence of hypercalcemia in a cohort of bipolar patients (BP) with and without concomitant lithium treatment and to study surgical outcomes for lithium-associated hyperparathyroidism. METHODS: Retrospective data, including laboratory results, surgical outcomes and medications, were collected from 313 BP treated with lithium from two psychiatric outpatient units in central Sweden. In addition, data were collected from 148 BP without lithium and a randomly selected control population of 102 individuals. Logistic regression was used to compare odds of hypercalcemia in these respective populations. RESULTS: The prevalence of lithium-associated hypercalcemia was 26%. Mild hypercalcemia was detected in 87 out of 563 study participants. The odds of hypercalcemia were significantly higher in BP with lithium treatment compared with BP unexposed to lithium (adjusted OR 13.45; 95% CI 3.09, 58.55; p = 0.001). No significant difference was detected between BP without lithium and control population (adjusted OR 2.40; 95% CI 0.38, 15.41; p = 0.355). Seven BP with lithium underwent surgery where an average of two parathyroid glands was removed. Parathyroid hyperplasia was present in four patients (57%) at the initial operation. One patient had persistent disease after the initial operation, and six patients had recurrent disease at follow-up time which was on average 10 years. CONCLUSION: The high prevalence of LAH justifies the regular monitoring of calcium homeostasis, particularly in high-risk groups. If surgery is necessary, bilateral neck exploration should be considered in patients on chronic lithium treatment. Prospective studies are needed.

Lithium-Associated Hyperparathyroidism: A Pooled Analysis.

BACKGROUND: Lithium treatment has been associated with hyperparathyroidism (HPT). However, there are conflicting data regarding the rate of single- (SGD) versus multiple-gland disease (MGD) as well as the optimum surgical approach in these cases. METHODS: Published data were identified through systematic electronic literature searches. Studies that fulfilled the preset inclusion criteria were analyzed (n = 12). RESULTS: These studies documented 210 lithium-associated HPT (LAH) cases. Of these, 103 (49%) were due to SGD and 107 (51%) due to MGD. The unadjusted odds ratio of having multiple LAH compared to sporadic HPT was 3.44 (95% confidence interval 2.5907-4.5633; p < 0.0001). The sensitivity of preoperative sestamibi and sonography for SGD was 66-100 and 75-82%, respectively. The sensitivity for MGD was 9-67% for both. Intraoperative parathyroid hormone monitoring was utilized in 6 studies. Three studies recommended minimally invasive parathyroidectomy (MIP), while the other 3 recommended bilateral exploration. CONCLUSION: LAH is a relatively frequent condition among patients on lithium, and calcium monitoring should be performed initially and longitudinally. Almost half of the LAH cases are due to SGD. MIP should be the optimum surgical approach.

Surgical approach and outcomes in patients with lithium-associated hyperparathyroidism.

BACKGROUND: Patients receiving lithium therapy are at elevated risk of developing hyperparathyroidism. In lithium-associated hyperparathyroidism (LAH), the incidence of multiglandular disease (MGD) is unclear, and the need for routine bilateral cervical exploration remains controversial. Therefore, in LAH patients, surgical approaches, pathologic findings, cure rates, and factors associated with persistent or recurrent disease were investigated. METHODS: Retrospective analysis of 27 patients with LAH undergoing parathyroidectomy with the intraoperative parathyroid hormone (PTH) assay. RESULTS: The median postoperative follow-up was 7 months; 17 patients had >6 months follow-up. Cervical exploration was unilateral in 9, bilateral in 18 (3 were converted from unilateral). Sixteen patients (62%) had MGD, 12 with four-gland hyperplasia and 4 with double adenomas. Ten patients (38%) had a single adenoma. Twenty-five (93%) of 27 patients had initially successful surgery. Of the 17 patients with >6 months follow-up, two had persistent disease and two experienced recurrent disease. All patients with a single adenoma remain free of disease. Three (75%) of four patients with persistent/recurrent disease had MGD and were receiving lithium at the time of surgery. Patients with persistent/recurrent disease were older (p = 0.01) and had experienced a longer duration of hypercalcemia (p = 0.04). CONCLUSIONS: LAH patients have a high incidence of MGD, and bilateral exploration is frequently necessary. With access to the intraoperative PTH assay, it is reasonable to initiate a unilateral approach because many patients will harbor single adenomas and can be reliably rendered normocalcemic. Patients with MGD remain at higher risk of persistent/recurrent disease.

Tenofovir-induced osteopenia and hyperparathyroidism: A case report and literature review.

Tenofovir disoproxil fumarate is the first-line antiviral therapy for chronic viral hepatitis B, but long-term use is associated with renal failure and hypophosphatemic osteomalacia. Tenofovir disoproxil fumarate-induced osteoporosis and secondary hyperparathyroidism are less commonly reported. Herein, we describe the case of a patient with bone and multijoint pain who was initially misdiagnosed as having normocalcemic primary hyperparathyroidism associated with prolonged exposure to tenofovir disoproxil fumarate. The patient's 24-h urinary calcium and phosphorus excretion levels and serum calcium levels were at the lower end of the normal range. After reviewing these findings, the diagnosis was amended to osteoporosis and secondary hyperparathyroidism caused by tenofovir disoproxil fumarate. In this report, we describe the differences in clinical and laboratory manifestations of hyperparathyroidism induced by tenofovir disoproxil fumarate and normocalcemic primary hyperparathyroidism. We also discuss relevant pathophysiological mechanisms and propose a feasible treatment strategy.

Lithium-associated hyperparathyroidism: surgical strategies in the era of minimally invasive parathyroidectomy.

BACKGROUND: Lithium remains an effective treatment of bipolar affective disorder. The long-term use of lithium is associated with an alteration in parathyroid function that may culminate in hyperparathyroidism. The long-term effects of lithium use are variable due to its complex effects on calcium homeostasis and bone metabolism, and as a consequence the indications for surgery remain poorly defined. The optimal surgical strategy for lithium-associated hyperparathyroidism in the era of minimally invasive surgery is also the subject of debate. The aim of the present study was to evaluate the variable findings of lithium-associated parathyroid disease. METHODS: A retrospective review was performed of patients undergoing parathyroid surgery presenting with lithium-associated hyperparathyroidism from July 1999 until July 2009 at the university hospital La Timone, Marseille, and from October 2005 to July 2009 at Hammersmith Hospital, Imperial College, London. Fifteen patients underwent surgery for lithium-associated hyperparathyroidism. Clinical data including patient demographics, duration of lithium use, clinical manifestations of hyperparathyroidism, indications for surgery, and biochemical parameters preoperatively and postoperatively were reviewed. Preoperative imaging, the surgical procedure performed, operative findings, and histopathology were also analyzed. RESULTS: All 15 patients had preoperative imaging: sestamibi scanning showed that 10 patients had localized single-gland disease, 1 had multiple hot spots, and 4 had a negative scan. Ultrasonography demonstrated a single abnormal gland in 8 patients and multiple enlarged glands in 1 patient; the test was negative in 6. As a consequence of concordant preoperative imaging a minimally invasive approach (endoscopic or a focused lateral approach) was adopted in 3 patients. Focused surgery demonstrated an enlarged hyperplastic gland in 3 cases and resulted in normocalcemia in the immediate postoperative period. However, one patient has a serum calcium at the upper limit of normal and elevated parathyroid hormone (PTH) levels, suggestive of possible recurrence of disease at 15 months follow-up. One patient has permanent hypoparathyroidism. In those patients who had open procedures, final histology showed hyperplastic multiglandular disease in 10 patients (83.3%) of patients and single-gland disease in 2 patients (16.7%). None of these patients show evidence of recurrence at follow-up. CONCLUSIONS: Lithium hyperparathyroidism is predominantly a multiglandular disease characterized by asymmetrical hyperplasia that is frequently associated with misleading or discordant localization studies. Bilateral neck exploration is therefore recommended in order to minimize the risk of disease recurrence.

Single Centre Experience in Patients with Primary Hyperparathyroidism: Sporadic, Lithium-associated and in Multiple Endocrine Neoplasia.

PURPOSE: It is assumed that primary hyperparathyroidism (pHPT) in Multiple Endocrine Neoplasia (MEN) and lithium-associated pHPT (LIHPT) are associated with multiple gland disease (MGD), persistence and recurrence. The studies purpose was to determine frequencies, clinical presentation and outcome of sporadic pHPT (spHPT), LIHPT and pHPT in MEN. Additional main outcome measures were the rates of MGD and persistence/recurrence. METHODS: Retrospective analysis of medical records of 682 patients with pHPT who had attended the University Hospital of Marburg between 01-01-2004 and 30-06-2013. All patients were sent a questionnaire asking about their history of lithium medication. RESULTS: Out of 682 patients, 557 underwent primary surgery (532 spHPT, 5 LIHPT, 20 MEN), 38 redo-surgery (31 spHPT, 7 MEN), 55 were in follow-up due to previous surgery (16 spHPT, 1 LIHPT, 38 MEN) and 37 were not operated (33 spHPT, 1 LIHPT, 3 MEN). Primary surgeries were successful in 97.4%, revealed singular adenomas in 92.4%, double adenomas in 2.9% and MGD in 3.4% of the cases. Rates of MGD in MEN1 (82.35%) were significantly higher than in spHPT (3.8%), while there was no significant difference between LIHPT (20%) and spHPT. Rates of persistence/recurrence did not significantly differ due to type of surgery (bilateral/unilateral) or type of HPT (spHPT/LIHPT/MEN). CONCLUSIONS: History of lithium medication is rare among pHPT patients. While MGD is common in MEN1, rates of MGD, persistence or recurrence in LIHPT were not significantly higher than in spHPT.

Focused parathyroidectomy with intraoperative parathyroid hormone monitoring in patients with lithium-associated primary hyperparathyroidism.

BACKGROUND: Lithium-associated hyperparathyroidism has been attributed to multigland hyperplasia requiring bilateral exploration and subtotal parathyroidectomy. Recent studies suggest that some patients may have single gland disease and be eligible for minimally invasive parathyroidectomy. METHODS: We performed a retrospective review of a prospective, single institution parathyroid database of 1,010 patients who underwent parathyroidectomy between December 1999 and October 2010. RESULTS: Nineteen patients with a history of lithium therapy and sporadic hyperparathyroidism were identified. Median age was 50 years (16-68); median duration of therapy was 19 years (1-37); 11 (58%) were on active therapy with lithium for multiple reasons. Preoperative median serum calcium was 10.9 mg/dL (10.0-12.3), median parathyroid hormone was 111 pg/mL (60-186). A total of 18 patients underwent preoperative imaging. Of 12 patients with single-site localization, 6 (50%) underwent a minimally invasive parathyroidectomy, 2 (17%) underwent unilateral explorations, 1 (8%) underwent bilateral exploration, and 3 (25%) had concomitant thyroidectomies. Six patients did not localize and underwent bilateral exploration for multigland disease. One patient without preoperative imaging had single-gland disease. In all operations surgeons used intraoperative parathyroid hormone (IOPTH) monitoring and met intraoperative criteria. Median IOPTH decrease was 74% (54-86) in single-gland disease and 85% (76-95) in multigland disease. Median abnormal gland weight was 590 mg (134-6,750) in single-gland disease and 296 mg (145-2,170) in multigland disease. All patients were normocalcemic at a median follow-up of 19 months (2-118). CONCLUSION: Of 19 patients with lithium exposure, 6 (32%) had multigland disease. However, of the 13 (68%) patients with single gland disease, all 12 who had preoperative imaging had single-site localization. If localization suggests single gland disease, minimally invasive parathyroidectomy with IOPTH monitoring can be successfully performed.

Rabbit model of primary hyperparathyroidism induced by high-phosphate diet.

The objective of this study is to establish a new rabbit model of primary hyperparathyroidism (PHPT) induced by high-phosphate diet. One hundred twenty rabbits were divided into two groups of 60 each. The treatment group was fed a high-phosphate diet (Ca:P = 1:7) and the control group was given a normal animal diet (Ca:P = 1:0.7) for 1 to 6 mo. Serologic examinations, including parathyroid hormone (PTH), calcium and phosphorus levels, blood urea nitrogen, creatinine, and uric acid, and the histologic examination, including parathyroid, kidney, and bones, were performed at the end of each month for 6 mo. Compared with the control, serum PTH levels in the treatment groups were elevated at all six time points, whereas serum calcium levels were reduced, and serum phosphorus levels remain unchanged over the course of the first 3 mo. Serum calcium levels were increased, whereas serum phosphorus levels were reduced at 4, 5, and 6 mo. Parathyroid histopathological examination showed no change during the first month, whereas 60% of the animals exhibited mild hyperplasia starting at 2 mo, and 90% of the animals in the treatment group exhibited mild-to-moderate hyperplasia with gland enlargement starting from 3 mo through the end of the study. Histopathological examination of the kidneys showed no change at 1 mo, but focal parenchymal inflammation with calcium deposition was observed in the treatment groups at 2 to 6 mo. Fibrous tissue of the bone extended toward the cortex, and fibrosis was evident at the third month. The fibrous cells were found to be concentrated mainly on the inner and outer membranes of the bone cortex, and the amount of fibrous tissue increased as the disease progressed. We conclude that a new rabbit animal model of PHPT can be successfully created by the administration of a high-phosphate diet. This animal model can be used in various future studies related to PHPT.

[A rare differential diagnosis of primary hyperparathyreoidism - case 12/2011]. / Seltene Differenzialdiagnose des primären Hyperparathyreoidismus - Fall 12/2011.

HISTORY AND ADMISSION FINDINGS: A 51-year-old woman was admitted from a mental institution for evaluation of hypercalcemia. She was treated with lithium for a bipolar disorder since 25 years. She complained of polydypsia and polyuria. The physical examination findings were unremarkable up to manic symptoms. INVESTIGATIONS: Laboratory values showed elevated serum calcium and parathormone. Serum phosporus was within the normal range. Neck ultrasound revealed a goiter with one nodule in the right thyroid lobe and a suspected enlarged lower left parathyroid gland. The sesta-MIBI-scan failed to detect an adenoma. DIAGNOSIS, TREATMENT AND COURSE: In light of long-term treatment with lithium and negative MIBI-scan, lithium-associated- hyperparathyreoidism (LAH) was suspected. The patient refused further preoperative imaging studies, such as c-11 methionine positron emission tomography and thyroid scan. Until surgery after stabilization of the psychiatric condition, treatment with the calcimimetic cinacalcet was initiated. CONCLUSIONS: Long-term lithium therapy is frequently associated with LAH. The criteria of diagnosis and therapy are similar to those of primary hyperparathyroidism. Lithium alters the set-point of the calcium-sensing-receptor and results in elevation of parathormone und hyperplasia of the parathyroid glands. Patient with LAH have a higher prevalence of multiglandular disease compared with sporadic hyperparathyreoidism. Thus, the preoperative localization is challenging. After surgery recurrent or resistant disease is more frequent. The calcimimetic cinacalcet is a potential alternative for patients who have contraindications to surgery, refuse surgery, or experience recurrent disease after surgery.

Long-term lithium therapy leading to hyperparathyroidism: a case report.

PURPOSE: This paper reviews the effect of chronic lithium therapy on serum calcium level and parathyroid glands, its pathogenesis, and treatment options. We examined the case of a lithium-treated patient who had recurrent hypercalcemia to better understand the disease process. CONCLUSION: Primary hyperparathyroidism is a rare but potentially life-threatening side effect of long-term lithium therapy. Careful patient selection and long-term follow-up can reduce morbidity. PRACTICAL IMPLICATIONS: As much as 15% of lithium-treated patients become hypercalcemic. By routinely monitoring serum calcium levels, healthcare providers can improve the quality of life of this patient group.