A Patient With the MEN1-Associated Hyperparathyroidism, Responsive to Cinacalcet

Alberto Falchetti; Antonio Cilotti; Luca Vagelli; Laura Masi; Antonietta Amedei; Federica Cioppi; Francesco Tonelli; Maria Luisa Brandi


Nat Clin Pract Endocrinol Metab. 2008;4(6):351-357. 

In This Article

Summary and The Case

Background: A 30-year-old woman with suspected multiple endocrine neoplasia type 1 (MEN1) was referred to our center in 2001 with primary hyperparathyroidism caused by a multiglandular parathyroid adenoma. The patient also had hyperprolactinemia caused by an anterior pituitary macroadenoma. The patient underwent a parathyroidectomy with autotransplantation of parathyroid fragments into the nondominant forearm, resulting in resolution of the primary hyperparathyroidism. MEN1 was confirmed by analysis of the MEN1 gene, which revealed a 1555insG frameshift mutation. In 2006 serum calcium and parathyroid hormone (PTH) levels were again found to be high.
Investigations: After parathyroidectomy in 2001, the patient underwent regular measurements of PTH levels from both forearms, of serum calcium, prolactin and phosphate levels, and of urinary calcium and phosphate levels. When serum calcium and PTH levels were found to be elevated in 2006, circulating PTH levels were similar in both forearms. Ultrasound scan and technetium-99m-labeled hexakis-2-methoxyisobutylisonitrile (99mTc MIBI) scintigraphy evidenced a metabolically active parathyroid nodule in the neck.
Diagnosis: Local recurrence of a parathyroid adenoma associated with MEN1.
Management: Because the patient refused a further operation, we decided to initiate pharmacological treatment with cinacalcet. After 1 month of therapy, serum calcium and PTH levels returned to normal. The patient has now been closely monitored for 1 year. During this time calcium and PTH levels remained normal, morphologically the parathyroid nodular lesion remained unchanged and cinacalcet was well tolerated without the occurrence of adverse events. Cinacalcet could represent an important pharmacological intervention in MEN1-associated primary hyperparathyroidism before surgery and in postsurgical recurrences.

In 2001 a 30-year-old woman was referred to our center with hypercalcemia caused by primary hyperparathyroidism and with hyperprolactinemia caused by a macroprolactinoma (1.2 cm in diameter on MRI). Her family history revealed that her father had multiple endocrine neoplasia type 1 (MEN1) and that her paternal uncle, who had died from complications of multiple duodenal ulcers, had been diagnosed with this syndrome as well. The patient was, therefore, also suspected of having MEN1, and this diagnosis was confirmed by germline mutational analysis of the MEN1 gene, which revealed a 1555insG frameshift mutation.[1]

Parathyroid scintigraphy using technetium-99m-labeled hexakis-2-methoxyisobutylisonitrile (99mTc MIBI) identified three areas of hyperfunctioning parathyroid tissue, and a neck ultrasound showed an elongated hypoechoic oval area (6x3 mm) at the inferior pole of the left thyroid lobe, the Doppler flow pattern indicating a hypervascular lesion with increased diastolic flow. This observation was suggestive of parathyroid hyperplasia or of a parathyroid adenoma.

Dual energy x-ray absorptiometry (DXA) was performed at the lumbar spine and the total left hip to evaluate the patient's BMD. This investigation demonstrated osteopenia at the lumbar spine (BMD 0.869 g/cm2; T-score - 1.81; Z-score - 1.9) and osteoporosis at the left hip (BMD 0.578 g/cm2; T-score - 2.86; Z-score - 2.91). These results were in keeping with a history of longstanding asymptomatic primary hyperparathyroidism, predominantly affecting the cortical bone mass.

The patient was treated surgically with a parathyroidectomy and a transcervical thymectomy, with autotransplantation of parathyroid fragments into the brachioradialis muscle of the nondominant arm. Four parathyroid glands were removed and histological examination showed evidence of a parathyroid adenoma in two glands and nodular hyperplasia in one gland. No abnormalities were found on examination of the fourth gland. Intraoperative parathyroid hormone (PTH) assay revealed a decrease of PTH levels by approximately 85% compared with baseline levels (maximum PTH value 21.5 pmol/l; nadir 2.6 pmol/l 15 minutes after removal of the last parathyroid gland), indicating successful removal of all parathyroid glands.[2]

Postoperatively, the patient was prescribed calcium carbonate and calcitriol for 3 months. Serum calcium levels were within the normal range in the days following the neck surgery as well as at the monthly biochemical evaluations performed over the following 12 months. Serum prolactin levels were maintained within the normal range by oral cabergoline (Dostinex®, Pharmacia Italia SpA, Milan, Italy), 0.5 mg once a week. After the operation, the patient underwent regular biochemical testing, including the evaluation of circulating PTH levels by blood sampling from both forearms every 6 months. In addition, an ultrasound scan was performed annually at the neck and the forearm.

The patient was also monitored for the occurrence of other tumors associated with MEN1, and in 2003 total body scintigraphy using 111In-DTPA (indium-111-labeled diethylenetriamine penta-acetate) revealed the presence of a pancreatic lesion with elevated expression of somatostatin receptor subtype 2. Abdominal CT scan confirmed the presence of a pancreatic nodule of 1.5 cm diameter and showed a clinically asymptomatic <1 cm-diameter lesion of the left adrenal gland. Evaluation of neuroendocrine hormones, however, showed normal levels of parathyroid hormone, gastrin, insulin, C-peptide, glucagon, vasoactive intestinal peptide, pancreatic polypeptide, somatostatin, cortisol, adrenocorticotropic hormone, dehydroepiandrosterone, androstenedione, and aldosterone.

The patient became pregnant in 2004, and during her pregnancy cabergoline treatment was discontinued. Once the pregnancy was confirmed, in December 2004, the patient underwent strict follow-up, with biochemical assessments, including the evaluation of bone turnover markers, every 3 months. The only abnormalities observed during that time were an increased level of prolactin throughout the pregnancy (as the patient refused to take bromocriptine during the pregnancy), and hypercalciuria (>500 mg/24 h, >12.5 mmol/day) and decreased levels of serum phosphate (<2.2 mg/dl, <0.71 mmol/l) at 36 weeks of gestation. Levels of PTH, serum calcium and bone turnover markers were at the upper limit of the normal range. She experienced no problems during the delivery and post-partum period. She did not breastfeed and, therefore, carbegoline treatment could be re-started immediately.

After the pregnancy, in 2006, elevated levels of PTH (in the dominant and nondominant arms) and total serum calcium were observed ( Table 1 ). Neck ultrasound showed a finely nonhomogeneous hypoechoic capsulated area with a maximal diameter of approximately 1 cm, with a vascular pole at the left lobe of the thyroid. We interpreted this as a local recurrence of primary hyperparathyroidism (Figure 1). In the same region, 99mTc-MIBI scintigraphy demonstrated hyperfunctioning parathyroid tissue (Figure 1). DXA was performed at the lumbar spine and left hip, revealing the presence of osteoporosis at the left hip (lumbar spine BMD 0.845 g/cm2, T-score - 2.21, Z-score - 2.25; total left hip BMD 0.551 g/cm2, T-score - 3.26, Z-score - 3.29). Pituitary MRI revealed a decrease in the size of the previously described macroprolactinoma by approximately 20%. Abdominal CT scan confirmed the presence of both the nodular pancreatic lesion and the <1 cm nodule of the left adrenal gland, which were unmodified compared with the previous examination.

The patient's neck ultrasound and technetium-99m-labeled hexakis-2-methoxyisobutylisonitrile (99mTc MIBI) parathyroid scintigaphy. (A) This ultrasound scan was performed 2 weeks before starting cinacalcet therapy. Inferiorly and externally to the left lobe of the thyroid gland, a finely nonhomogeneous hypoechoic capsulated area with a maximum diameter of approximately 1 cm and with a vascular pole can be seen. (B) After 1 year of treatment with cinacalcet the echographic lesion was unmodified, compared with Figure 1A. (C) Planar 99mTc-MIBI parathyroid scintigraphy scanning performed 1 week before starting cinacalcet therapy. (D) This depicts the late-phase image acquisition obtained by planar 99mTc-MIBI parathyroid scintigraphy. (E) A 99mTc sestamibi-single-photon emission computed tomographic (sestamibi-SPECT) scan performed after 1 year of cinacalcet therapy. The white circles in (C), (D) and (E) indicate a focal area of increased tracer uptake adjacent to the medial side of the lower pole of the left thyroid lobe.

The patient refused re-operation of the parathyroid adenoma and we, therefore, decided to initiate pharmacological treatment with cinacalcet. The potential advantages, disadvantages and limitations of this treatment were well explained to the patient. Eight months after the delivery of her baby, and following the approval of the competent health authorities of the Tuscany Region and with of the patient's written informed consent, oral treatment with cinacalcet-HCl (Mimpara®, Amgen Inc., Thousand Oaks, CA) was initiated at a daily dose of 60 mg (30 mg twice daily). The patient developed gastric pain, and the dose of cinacalcet was subsequently reduced to 30 mg daily. The patient has experienced no adverse events associated with the use of the drug in 1 year of treatment.

Table 1 shows the full hormonal and biochemical profiles of the patient, starting 6 months before the treatment with cinacalcet and continuing up to 1 year afterwards. Parathyroid ultrasound scanning and scintigraphy were performed at baseline and after 12 months of treatment (Figure 1).

After 1 month of therapy with 30 mg daily of cinacalcet, a satisfactory control of calcium homeostasis was reached ( Table 1 ). Systemic PTH levels, measured by venous sampling from the right forearm (the one not harboring the parathyroid transplant) returned to the normal range after 1 month of treatment and remained stable for the following 12 months. Urinary calcium excretion over 24 h normalized after 2 weeks of cinacalcet therapy and remained normal for the following year. Serum phosphate levels returned to normal after 3 months' therapy. Bone alkaline phosphatase and urinary deoxypyridinoline levels were elevated at baseline but returned to normal after 6 months of therapy ( Table 1 ).

Cinacalcet therapy did not influence the levels of basal and secretin-stimulated gastrin secretion and did not influence the levels of the other GEP (gastro-entero-hepatic) hormones, apart from C-peptide, which was elevated at baseline but normalized within 2 weeks of treatment ( Table 1 ). Prolactin secretion remained suppressed by cabergoline treatment.

Neck ultrasound performed after 12 months of cinacalcet therapy confirmed the presence of a parathyroid enlargement. The size and echographic features of this lesion remained unchanged compared with the ultrasound images obtained before treatment. Similarly, 99mTc-MIBI parathyroid scintigraphy confirmed hyperfunctioning parathyroid tissue (Figure 1). DXA showed that BMD had improved by 4.7% at the lumbar spine and by 17.8% at the left hip. Finally, 111In-DTPA total body scintigraphy confirmed the presence of a pancreatic lesion that had remained unchanged compared with the examination performed before starting cinacalcet treatment. The patient's BMI at baseline was 23.2 kg/m2 and remains unchanged after 1 year of treatment (22.4 kg/m2). After 1 year of cinacalcet therapy, the treatment is continued under strict clinical and biochemical follow up.


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