Primary Hyperparathyroidism: A Case-based Review

Primary hyperparathyroidism (PHPT) is most often detected as hypercalcemia in an asymptomatic patient during routine blood work. Knowing the appropriate work-up of hypercalcemia is essential, since untreated PHPT can have significant complications affecting multiple organ systems—most notably, renal and musculoskeletal. Parathyroidectomy is curative in up to 95% of cases, but prevention of long-term complications relies on prompt recognition and appropriate follow-up.

Primary hyperparathyroidism (PHPT) is a common endocrine disorder, with a prevalence of approximately 1 to 3 cases per 1,000 persons.¹ PHPT results from inappropriate overproduction of parathyroid hormone (PTH), the primary regulator of calcium homeostasis, and is characterized by hypercalcemia in the setting of an elevated or high-normal PTH level. In most cases of PHPT, unregulated PTH production is caused by a single parathyroid adenoma.

PHPT is the most common cause of hypercalcemia in outpatients and is typically diagnosed following incidental discovery during routine blood work in an asymptomatic patient.^1,2 It is two to three times more common in women than in men, and incidence increases with age; as such, postmenopausal women are most commonly affected.^1,3 PHPT often has an insidious course, and recognition of its clinical manifestations followed by appropriate diagnostic work-up and management are necessary to prevent sequelae.³

PATIENT PRESENTATION

A 68-year-old Caucasian woman presented to her family practice office for a third visit with continued complaints of nontraumatic right lower leg pain. She had previously been diagnosed with tendonitis, which was treated conservatively. The pain failed to improve, and an x-ray was ordered. The x-ray revealed no acute findings but did show osteopenia, prompting an order for a bone mineral density (BMD) test. The BMD test demonstrated osteoporosis, which warranted further investigation. She was prescribed alendronate but refused it, against medical advice, due to concern over potential adverse effects.

Her medical history included hyperlipidemia and hypertension under fair control with lisinopril. She took a low-dose aspirin and flaxseed supplement daily. She also had a history of radiation to the neck, having undergone tonsillar irradiation as a child (a common practice from the 1930s through the 1950s).³ Surgical history included a total hysterectomy with bilateral salpingo-oophorectomy, appendectomy, and tonsillectomy. There was no personal or family history of cancer or endocrine disorders, hypercalcemia, or nephrolithiasis. She was up to date on vaccines and preventive health care measures. Allergies included penicillin and sulfa, both resulting in hives. She was a nonsmoker and did not drink alcohol or engage in illicit drug use.

Review of systems revealed right lower anterior leg pain for four months, characterized as aching, deep, sharp, and throbbing with radiation to the ankle. The pain was worse with activity and prolonged standing; ibuprofen and application of ice provided partial relief. She had experienced some mood changes, including irritability. Physical exam was normal except for dominant right-sided thyromegaly, marked bony point tenderness to the right midshin area, and an antalgic gait.

Laboratory work-up demonstrated elevated PTH, alkaline phosphatase, and calcium levels and a low 25-hydroxyvitamin D [25(OH)D] level (see Table 1). MRI of the right lower leg revealed a grade IV stress fracture (see Figure 1). The elevated serum calcium and PTH levels in addition to abnormal bone density findings led to the diagnosis of PHPT. She was referred to endocrinology and orthopedics for management of PHPT and the stress fracture, respectively, and was placed in an orthopedic walking boot for treatment of the midtibial stress fracture.

The endocrinologist referred her to an otolaryngologist trained in the surgical management of parathyroid adenomas, who ordered a thyroid ultrasound; this study was inconclusive. Additional imaging, including a Tc-99m sestamibi parathyroid scan and CT with contrast of the soft tissue of the neck, was obtained. The parathyroid scan of the neck and upper chest showed retained activity in the right inferior thyroid pole that was concerning for a parathyroid adenoma (see Figure 2). The CT identified a 1.5-cm parathyroid adenoma off the right inferior pole of the thyroid gland (concordant with the parathyroid scan). A single 300-mg parathyroid adenoma was removed from the right inferior pole of the thyroid. The surgery was deemed successful, with intraoperative normalization of the PTH level.

The patient was managed postoperatively by the endocrinologist and was started on calcium and vitamin D supplements. She was prescribed a bisphosphonate, as she had refused to take alendronate following her abnormal BMD test.

DIFFERENTIAL DIAGNOSIS

PHPT and malignancy are the most common causes of hypercalcemia, accounting for 90% of cases.^2,4 A less common cause is familial hypocalciuric hypercalcemia (FHH), a rare benign disorder that imitates PHPT.¹ FHH is ruled out by measurement of 24-hour urine calcium excretion and is characterized by hypocalciuria, defined as a urine calcium level of less than 100 mg/24 h (reference range, 100-300 mg/24 h).² Low calcium excretion can also be identified by a calcium-creatinine excretion ratio.² FHH is a benign autosomal dominant condition caused by a heterozygous mutation of the parathyroid glands’ calcium-sensing receptors.^2,5,6 Young adults with FHH are asymptomatic, and mild hypercalcemia and a normal or slightly elevated PTH are the only laboratory findings.⁴