Hypercalcemia Appeared in a Patient with Glucagonoma Treated with Octreotide Acetate Long-acting Release

Rui Min,Mei Li,Jiang-feng Mao,Feng Gu,Hui-juan Zhu,Wen-hui Li,and Yu-xiu Li＊

Department of Endocrinology,Key Laboratory of Endocrinology of the Ministry of Health,Peking Union Medical College Hospital,Chinese Academy of Medical Sciences &Peking Union Medical College,Beijing 100730,China

PABCREATIC neuroendocrine tumours are uncommon neoplasms of the pancreas.They may cause a clinical syndrome due to hormone overproduction.Glucagonoma is a rare kind of pancreatic tumors.Here we report a case of glucagonoma.Hypercalcemia occurred when the patient underwent octreotide acetate long-acting release.

CASE DESCRIPTION

A 45-year-old woman presented with glossitis in 2003 and rashes on her upper arm in 2004.Meanwhile,she had stomachache and repeated confusion 3 hours after breakfast.The computed tomography scan showed multiple high-signal-intensity space-occupying lesions in the liver.A 75-g,3-hour oral glucose tolerance test (OGTT)was taken in December 2004 and January 2005,respectively,and the results showed the patient had impaired glucose tolerance with normal serum insulin level and serum glucagon level was beyond the normal reference range (Table 1).The somatostatin receptor imaging with octreotide showed a high concentration of somatostatin receptors were present in both the tail of the pancreas and the liver.The diagnosis of glucagonoma was made.

She underwent pancreatectomy and splenectomy in January 2005.The final pathological diagnosis was a well-differentiated neuroendocrine carcinoma of the pancreas.Immunohistochemical staining showed the lesion was glucagon-positive.Serum glucagon level was analyzed once a day for successive 3 days after the operation,which was decreased to 119,187,and 160 pg/mL.The symptoms of reactive hypoglycemia relieved.Serum calcium level was 2.45 mmol/L in August 2005 before she received other treatments.In March 2006,the serum glucagon level raised (Table 2).

Computed tomography of the abdomen in April 2006 showed a hepatic metastatic lesion.She received octreotide acetate long-acting release (Sandostatin LAR Depot,Novartis Pharma Schweiz AG,Switzerland) at a dose of 20 mg every 28 days.This regimen lasted regularly for two years,and her glucagon level was monitored in a range of 100.31-284.55 pg/mL.

In May 2008,the symptoms of glossitis and necrolytic migratory erythema emerged again,so the dose of octreotide acetate long-acting release changed to 20 mg every 21 days.But her glucagon level remained high(230.36-295.38 pg/mL).Glossitis and rashes disappeared for just about 10 days after the injection of octreotideacetate long-acting release then emerged again.In December 2008,white rashes appeared on the upper arm and red exelcosis on the right side of the tongue.Serum glucagon level was 365.0 pg/mL.The dose of octreotide acetate long-acting release was increased to 20 mg every 14 days,which lasted for about five months until March 2009.Meanwhile,her serum calcium level increased to 2.76 mmol/L (normal range is 2.13-2.70 mmol/L),without a complaint of ostealgia and any treatment.Serum calcium level was retested in October 2009 and the result was 3.07 mmol/L.The serum parathyroid hormone (PTH) level was lower than 3.00 pg/mL,which was below the normal range.The serum ionized calcium level was 1.43 mmol/L.Calcium and phosphate contents were 252 mg and 502.2 mg respectively in a urine sample that was collected over 24 hours,both of which were in the normal range.Bone scan in December 2009 showed an abnormal concentration of the isotope in the total skeleton,which was considered to be metabolic bone disease.

Table 1.Results of 75-g,3-hour oral glucose tolerance test in December 2004 and January 2005

Table 2.Results of 5-hour oral glucose tolerance test in March 2006

Without any treatment,in January 2010 serum biochemical test showed a serum calcium of 3.11 mmol/L,ionized calcium of 2.76 mmol/L,phosphorus of 1.25 mmol/L,25-(OH)-VitD3 of 10.7 ng/mL,and PTH level being below 3.00 pg/mL.Bone density test showed she had osteoporosis.She was treated with zoledronic acid injection 4 mg once per year to reduce the calcium level.Two weeks later,the calcium level was decreased to 2.56 mmol/L,and four weeks later to 2.41 mmol/L.The patient seemed to have jaw pain,which might be caused by zoledronic acid,so zoledronic acid was not administrated again.The serum calcium levels were 2.87 mmol/L in May 2010 and 2.9 mmol/L in July 2010.Now the patient is still followed up without any treatment for hypercalcemia.The dose of octreotide acetate long-acting release maintained 20 mg every 14 days to 21 days depending on the symptoms of rash.

DISCUSSION

Glucagonoma is a rare pancreatic tumor.As liver metastasis exists in more than 50% of the patients at the diagnosis of this tumor,1besides surgical ablation of the primary tumor,endocrine therapy is extremely important.2-4Adamset al5demonstrated once metastasis exists in the liver or lymph nodes,the mean survival rate of patients with glucagonoma is 2.5-3 years.It has been proven the treatment regime for the glucagonoma patient is quite efficient because she is still alive 6 years after treatment with octreotide acetate long-acting release.

It has revealed that kinds of somatostatin receptors are expressed on the pancreatic endocrine tumor cell(sst1-5).6The anti-proliferative effect including inducing apoptosis of the tumor cells exhibits while somatostatin binds to these receptors.7-11Somatostatin analog octreotide is widely used in the diagnosis and treatment of pancreatic neuroendocrine carcinoma.4,12The action of longacting release regimens will last four weeks after injection.The adverse reactions of octreotide acetate long-acting release include gastrointestinal reaction,gallstones formation,hyperglycemia,and hepatic function damage,etc.

As octreotide acetate long-acting release at a dose of 20 mg every 28 days or 20 mg every 21 days did not sufficiently control the symptoms of glossitis and rashes in this case,so we changed the dose to 20 mg every 14 days that could efficiently control the gossitis and rashes.There is no literature that reported the relationship between the hypercalcemia and higher dosage of octreotide acetate long-acting release.When hypercalcemia occurred,serum phosphorus and 25-(OH)-VitD3levels of the patient were in the normal range,and PTH level fell below the normal range due to hypercalcemia.The diagnosis of hyperparathyroidism was not supported by available data.And the result of bone scan did not support the diagnosis of the constitutional bone neoplasm or tumor bone metastasis being the cause of hypercalcemia.The high dose of octreotide supplementation might be the most reasonable cause of hypercalcemia for this case.Pharmacologically,upon binding of octreotide to its receptors,octreotide will show its inhibitory effects on adenylate cyclase and influx of calcium,13which might cause the hypercalcemia.The mechanism still needs to be investigated.

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