Case Report

SPONTANEOUS REMISSION OF PRIMARY HYPERPARATHYROIDISM RELATED TO AN AUTOIMMUNE DISEASE: A CASE REPORT Barbara C. Silva, MD, PhD; Jessica Fleischer, MD; Zachary Lenane, BS; Wen-Wei Fan, MPH; Donald J. McMahon, MS; John P. Bilezikian, MD ABSTRACT Objective: To report the unusual case of a woman with unequivocal primary hyperparathyroidism (PHPT) for 13 years who experienced spontaneous remission of her disease concomitant with the diagnosis of psoriatic arthritis. Methods: Clinical presentation, clinical course over 23 years of follow-up, and review of the pertinent literature are presented. Results: A 42-year-old woman was referred for evaluation of persistent hypercalcemia 2 months after unsuccessful parathyroid surgery for PHPT, in which a single, hyperplastic parathyroid gland was removed. Further evaluation confirmed persistent PHPT evidenced by hypercalcemia (12.1 mg/dL), elevated parathyroid hormone (PTH) level (118 pg/mL), normal calcium urinary excretion, and increased bone turnover markers. Persistent hypercalcemia and serum levels of PTH above normal were observed for 11 years after the parathyroid surgery. Thereafter, the patient experienced a downward trend and ultimate normalization of her serum calcium and PTH, which was associated, remarkably, with the development of psoriatic arthritis. Since return to normal of the serum calcium and PTH levels, the PHPT remission has persisted for 10 years without any signs of recurrent disease.

Submitted for publication July 30, 2014 Accepted for publication December 23, 2014 From the Metabolic Bone Diseases Unit, Division of Endocrinology, Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, New York. Address correspondence to Dr. John P. Bilezikian, College of Physicians and Surgeons, 630 West 168th Street, New York, NY 10032. E-mail: [email protected]. DOI: 10.4158/EP14353.CR To purchase reprints of this article, please visit: www.aace.com/reprints. Copyright © 2015 AACE.

Conclusion: Spontaneous remission of PHPT is exceedingly rare, and when it occurs, it is usually related to parathyroid hemorrhage or infarction. The patient’s clinical course was not characteristic of parathyroid hemorrhage or infarction, and the concomitant appearance of psoriatic arthritis, an autoimmune disease, raises the possibility of an immune-mediated process explaining this outcome. (AACE Clinical Case Rep. 2015;1:e255-e259) Abbreviations: BMD = bone mineral density; CaSR = calcium-sensing receptor; NALP5 = NACHT leucine-rich-repeat protein 5; NSAIDS = nonsteroidal anti-inflammatory drugs; PHPT = primary hyperparathyroidism; PTH = parathyroid hormone INTRODUCTION Primary abnormalities of the parathyroid glands, associated with hypersecretion of parathyroid hormone (PTH), define the common endocrine disorder, primary hyperparathyroidism (PHPT). A solitary, benign parathyroid adenoma is found in approximately 80% of patients with PHPT (1). In patients who meet surgical criteria and agree to parathyroid surgery, a single parathyroid adenoma can be readily identified pre-operatively by a variety of imaging modalities, after which, minimally invasive parathyroid surgery with intra-operative PTH monitoring is associated with a >95% success rate (2). In patients who do not have parathyroid surgery, natural history studies have invariably shown that the disease persists and that complications can ensue (3). Spontaneous remissions are rare, but when they occur, they are usually due to infarction or hemorrhage into or around the hyperfunctioning parathyroid tissue (4-7). Another possible explanation for spontaneous remission of the disease

AACE CLINICAL CASE REPORTS Vol 1 No. 4 Autumn 2015 e255

e256 Spontaneous Remission of PHPT, AACE Clinical Case Rep. 2015;1(No. 4)

would be the development of anti-parathyroid antibodies (8). We report a patient who experienced spontaneous remission of PHPT 11 years after unsuccessful surgery in which 1 abnormal parathyroid gland was removed. The gradual, complete resolution of the hypercalcemia and return to normal of the elevated PTH level was associated with the development of psoriatic arthritis, an autoimmune disease, prompting the possibility that an autoimmune process could have been responsible for this permanent, nonsurgical cure of the disease. CASE REPORT A 42-year-old woman was referred for evaluation of persistent hypercalcemia 2 months after unsuccessful parathyroid surgery for PHPT. Her serum calcium and PTH prior to surgery were elevated, at 11.2 mg/dL (normal, 8.6 to 10.2 mg/dL) and 116 pg/mL (normal, 10 to 65 pg/mL), respectively. Serum phosphorus was 3.1 mg/dL (normal, 2.5 to 4.5 mg/dL), and the total alkaline phosphatase activity was normal, at 121 U/L. Bone mineral density (BMD) by dual energy X-ray absorptiometry showed T-scores of −3.0 at the lumbar spine, −2.2 at the femoral neck, and −1.2 at the distal one-third radius. A 0.8-cm lesion consistent with an enlarged parathyroid gland at the posterior right lobe of the thyroid was seen by magnetic resonance imaging. At the time of parathyroidectomy, the right superior parathyroid gland, weighing only 40 mg, was removed. The other 3 parathyroid glands were identified as normal, but they were not biopsied. Extensive exploration of the neck and the mediastinum did not reveal any other parathyroid tissue. Pathology confirmed the identity of a hyperplastic parathyroid gland. Serum calcium remained elevated, at 11.8 mg/dL, 24 hours after the surgery. When she was seen in our Metabolic Bone Diseases unit, noteworthy aspects of her medical review include a total abdominal hysterectomy and bilateral oophorectomy 2 years earlier for uterine leiomyoma and ovarian cancer, which was coincident with the diagnosis of hypercalcemia. Family history was positive for arthritis but negative for any disorders of calcium metabolism. Physical examination was unremarkable. Her medication included conjugated estrogen, 0.3 mg daily. Further evaluation confirmed persistent hypercalcemia (12.1 mg/dL) and an elevated PTH level (118 pg/mL). 25-hydroxyvitamin D level was 37 ng/mL (normal, 30 to 100 ng/mL), and her 1,25-dihydroxyvitamin D level was 83 pg/mL (normal, 15 to 65 pg/mL). Her 24-hour urine calcium excretion was 185 mg. Serum osteocalcin and urinary deoxypiridinoline were elevated, at 17.6 ng/mL (normal, 1.6 to 9.2 ng/mL) and 31.4 pmol/µmol creatinine (normal, 4 to 21 pmol/µmol creatinine), respectively. Serum albumin and hepatic and kidney function tests were normal. Further parathyroid surgery was not pursued, a decision made by the patient.

During the first 11 years of her follow-up, she remained hypercalcemic, with serum calcium values ranging between 10.3 and 12.5 mg/dL. Serum PTH levels continued to be above normal, ranging from 63 to 125 pg/ mL (Fig. 1 A, B). During the first 5 years after surgery, the PTH level remained over 100 pg/mL, whereas the serum calcium showed a small decline. In July of 1997, 5 years after the parathyroidectomy, a serum PTH level of 76 pg/ mL was detected. This level was 3 SD below the mean of previous values and, thus, was considered to be statistically different from the previous PTH concentrations (9). From that point forward, PTH levels continued to trend downward. While still elevated, the serum calcium remained stable and the phosphorus followed an upward trend (Fig. 1 C). BMD was low but unchanged. In 1998, conjugated estrogens were replaced by raloxifene. She reported no neck trauma, further neck surgery, general anesthesia, nor any episodes of hypotension. In February of 2003, 11 years after surgery, normal levels of serum calcium and PTH were detected for the first time (Fig. 1 A, B). Concomitantly, serum phosphorus concentration followed an upward trend. During this period, the patient was still taking raloxifene, which was discontinued a few years later. The trend downward and ultimate normalization of the serum calcium and PTH was, remarkably, associated with the development of psoriatic arthritis. Symptoms of arthritis were first noted in 2001, when the patient started irregular use of nonsteroidal anti-inflammatory drugs (NSAIDs). In 2004, the psoriatic arthritis was evident by synovitis in multiple peripheral joints and contractures of the right elbow. The sedimentation rate was high, at 67 mm, and the C-reactive protein was 2.4 mg/L (normal range,