Pathology

Primary hyperparathyroidism (PHPT) is hypercalcemia secondary to excess PTH production from a dysfunctional gland or glands, and is the most common cause of hypercalcemia in the ambulatory setting. ³ Primary hyperparathyroidism affects roughly 1% of the adult population, and the incidence increases with age. Women are affected at least twice as often as men. ^{3 , 4 , 5 , 6} PHPT can be attributable to a single adenoma (80–90% of cases), four-gland hyperplasia (5–10%), double adenomas (4–6%), and rarely parathyroid carcinoma (< 1%) (Fig. 21.1 and Fig. 21.2). ^{7 , 8 , 9 , 10 , 11 , 12 , 13}

Genetic alterations have been shown to contribute to the development of primary hyperparathyroidism. Two specific genetic mutations have been demonstrated in nonfamilial parathyroid adenomas. ^{1 , 12 , 14 , 15 , 16} Decreased expression of the multiple endocrine neoplasia type 1 (MEN1) tumor suppressor gene has been found in up to 20% of these adenomas. Activation of the cyclin D1 (CCND1)/PRAD1 oncogene results in overproduction of cyclin D1 and is found in up to 40% of adenomas. Parathyroid adenomas with these genetic alterations are hypercellular and have calcium-sensing receptors that do not function properly.

The CaSR plays an important role in calcium homeostasis. This receptor is found in abundance on the surface of the normal parathyroid gland in addition to many other locations in the body, including the renal tubules, bone marrow, osteoclasts, breast tissue, parafollicular cells of the thyroid, and G cells in the gastric mucosa. Adenomatous cells have a decreased concentration of calcium-sensing receptors compared with normal cells, and have altered set points, which allow for inappropriate production of PTH despite normal or high serum calcium levels. ^{2 , 3 , 17 , 18 , 19}

Clinical Manifestations

The clinical spectrum of PHPT involves multiple organ systems. Renal manifestations are the second most common and occur in 20 to 30% of these patients. ⁷ Nephrolithiasis accounts for virtually all of the kidney-related complications. PTH increases renal calcium absorption, renal phosphorus excretion, and activity of 1α-Hydroxylase. 1 α-Hydroxylase converts vitamin D to its active form, which increases intestinal absorption of calcium. The excess of filtered calcium compared with that absorbed leads to hypercalciuria and the predisposition to calcium stones. Hyperparathyroidism also leads to a decrease in the glomerular filtration rate and a mild metabolic acidosis. Nephrocalcinosis is a rare complication of hyperparathyroidism and is diffuse calcification of the renal tubular system and parenchyma, which can be seen on a plain radiograph. ¹

Skeletal manifestations of PHPT are the most common when the symptom of bone pain is included. Osteitis fibrosis cystica, Brown’s tumors, and fractures were common presenting entities with hyperparathyroidism in the past. With earlier detection, these have often been replaced by osteopenia or generalized bone demineralization and bone pain. The osteopenia associated with PHPT continues to carry a fracture rate that is greater than that in controls. In the current form of the disease, this generalized bone loss cannot be visualized well on plain radiographs, but it can be identified early with bone densitometry. A dual energy X-ray absorptiometry (DEXA) scan is used to assess bone density and is typically reported for the lumbar spine, femoral neck, and distal radius. Hyperparathyroidism decreases bone density in cortical bone more than trabecular bone, and therefore the distal radius is often the most affected. The bone density is reported as a T-score, which gives the density as a standard deviation from normal, and a T-score of – 2.5 (the defining score for the start of osteoporosis) is often used as an indication for surgical intervention on the parathyroids. ^{2 , 4 , 20}

Gastrointestinal symptoms are less specific but are part of the clinical picture of HPT. Pancreatitis, peptic ulcer disease, constipation, nausea, and emesis have all been described. Gastroesophageal reflux is most commonly reported, although no clear mechanism has been demonstrated.

There are several “somatic” symptoms associated with HPT; they are nonspecific and include depression, impaired cognition, fatigue, malaise, sleep disorders, and irritability. Although these symptoms are difficult to characterize, they stress the importance of obtaining a thorough neuropsychiatric history since these symptoms have been shown to improve after correction of the underlying hyperparathyroidism. ^{4 , 7 , 21 , 22 , 23 , 24}

Evaluation

Primary hyperparathyroidism can be diagnosed with precision with a serum calcium level, serum PTH level, 24-hour urinary calcium and creatinine, and an adequate patient history. If the serum albumin levels are normal, total serum calcium is preferred and more reliable than ionized calcium. ²⁵ Assays that measure intact, biologically active PTH are preferred when compared with older methods of measuring fragments of the PTH molecule. An elevated serum calcium level in the presence of elevated levels of parathyroid hormone is virtually diagnostic for primary hyperparathyroidism. There are a few exceptions that need to be considered. Thiazide diuretics and lithium excess can produce laboratory findings similar to primary hyperparathyroidism and should be investigated in the patient history. ^{3 , 26} Twenty-four-hour urinary calcium and creatinine excretion is important in the evaluation of hyperparathyroidism. These laboratory results can rule out the possibility of a rare condition known as familial hypocalciuric hypercalcemia (FHH) (see discussion later in the chapter). ²⁰ Urinary calcium and creatinine excretion can also help with determining prognosis because total 24-hour calcium excretion > 400 mg/24 h is associated with an increase in renal complications. ⁴ Studies have also suggested a role for vitamin D testing, which can help with the evaluation of persistent elevation of PTH levels postoperatively and may help identify patients that are at risk for secondary HPT and postoperative hypocalcemia. ^{27 , 28 , 29}

All patients who are diagnosed with primary hyperparathyroidism by laboratory data warrant a DEXA scan to assess bone mineral density. This will determine the degree of secondary osteopenia and risk of impending fracture. Any patients who have nephrolithiasis with calcium stones, pathological fractures, or significant osteoporosis should be worked up for hyperparathyroidism with a serum calcium and PTH level to rule out hyperparathyroidism as a cause. ³

Management

The typical clinical presentation of PHPT has changed dramatically since its description in the 1920s. When this condition was first described, patients presented with the classic “renal stones, painful bones, abdominal groans, psychic overtones, moans, and fatigue.” ²⁷ With increased understanding of PHPT and the addition of calcium to routine metabolic panels, patients are now being identified much earlier in their clinical course. It is estimated that only 20 to 30% of contemporary patients with PHPT present with significant symptoms. ^{2 , 3 , 4 , 30} Many argue that a larger number of patients are actually symptomatic but present with nonspecific symptoms, including depression, fatigue, bone pain, or anorexia. This debate aside, 60 to 80% of patients who present with primary hyperparathyroidism presently are asymptomatic or have nonspecific symptoms. ^{2 , 7 , 30} This can leave practitioners with the therapeutic dilemma of which patients warrant treatment.

This dilemma has been the topic of meetings and recommendations from the National Institutes of Health (NIH) as well as the American Association of Clinical Endocrinologists and American Association of Endocrine Surgeons. It has been commonly accepted that patients presenting with classic symptoms of hyperparathyroidism, including fracture, nephrolithiasis, and neuromuscular complaints, warrant treatment. More recent reports have indicated that asymptomatic hyperparathyroid patients have a long-term increase in cardiovascular disease and malignancy. ^{4 , 29 , 30} Furthermore, 23 to 62% of patients who present without symptoms become symptomatic within 10 years of presentation. ⁴ For these reasons, in 2008 an NIH consensus panel met and modified its third consensus guidelines and recommended treatment for asymptomatic patients if any of the following apply: serum calcium is > 1 mg/dL above the normal range, age is < 50, creatinine is < 60 mL/min, the patient cannot participate in follow-up, severe psychoneurological disorder, or other complications of PHPT, including nephrocalcinosis or osteoporosis (T-score < – 2.5 standard deviation [SD] at the lumbar spine, hip, or wrist) (Table 21.1). ³⁰

An in-depth discussion of all the surgical and medical treatment options can be found in other chapters, so current treatment options and recommendations are only briefly addressed here. There are no long-term studies demonstrating the efficacy of medical management or observation in these patients. Several medications target the effects of hyperparathyroidism without treating the underlying problem. Bisphosphonates have been shown to increase bone mineral density in patients with hyperparathyroidism, with no significant effect on PTH levels. ³¹ Similarly, estrogen replacement can stabilize bone loss in postmenopausal women with PHPT. ³² Furosemide can help to reduce serum calcium levels acutely. Calcimimetic medications are an intriguing class of medications that target the problem in hyperparathyroidism. With their mimetic activity these medications give negative feedback on the calcium-sensing receptors of the parathyroids and can reduce PTH production. One of these medications, cinacalcet, has been shown to reduce PTH levels and normalize serum calcium. ^{33 , 34} Calcimimetics have shown promising results, and, although studies have found them to be less effective than the gold standard of parathyroidectomy at decreasing PTH levels, there are no statistically significant differences in calcium and phosphate levels between the two groups 1 month after treatment. ^{4 , 33}

If patients with PHPT are managed medically, they require clinical follow-up, biannual serum calcium levels, annual serum creatinine levels, and annual bone densitometry. ¹ Associated “somatic” symptoms may not abate with drug therapy, and patients incur the cost of chronic pharmacotherapy. ¹

The cost of follow-up after several years of medical management for primary hyperparathyroidism has been shown to exceed the costs of successful surgical management. ³⁵ Surgical management has been reported to be 95 to 98% curative, with complication rates of 1 to 2% in experienced hands. It is for these reasons that the recent position statement from endocrinologists and endocrine surgeons recommended surgical intervention in patients who meet the preceding criteria for treatment.

Parathyroid Carcinoma

Another cause of primary hyperparathyroidism that warrants discussion is parathyroid carcinoma (PTC) (Fig. 21.3). This is a rare condition that accounts for < 1% of hyperparathyroidism. It affects men and women equally, and the average age of presentation is 55 years.

One challenge is that the diagnosis is rarely apparent on initial presentation because the symptoms are the same as benign causes of hyperparathyroidism. Consistent findings in parathyroid carcinoma are preoperative calcium and PTH levels much higher than those typically found with benign disease. ³⁶ The calcium levels for PTC are often >14.0 mg/dL, and PTH levels are commonly > 300 ng/dL. The tumor itself is usually larger than the typical adenoma, on average measuring 2 to 3 cm in diameter. A palpable neck mass is present in up to 70% of patients found to have PTC, which is not characteristic of benign disease. ³⁷ Cervical lymphadenopathy, which should raise suspicion for a malignant process, is found in one-third of patients presenting with PTC. Patients with parathyroid carcinoma are also more commonly symptomatic. In contrast to reports of 20 to 30% of patients with primary hyperparathyroidism who present with symptoms, in one series eight of nine patients who were found to have parathyroid carcinoma intraoperatively had “somatic” symptoms at presentation. ^{16 , 36 , 37}

Intraoperative findings that are consistent with parathyroid carcinoma include adherence to or invasion of surrounding structures (thyroid lobe or strap muscles), fibrosis, nodularity, induration, and gray color instead of the typical tan adenoma. Careful attention to these characteristics is important during surgery because the treatment of choice for parathyroid carcinoma is wide surgical excision. Adjuvant treatments, such as external beam radiation and chemotherapy, have not been shown to improve survival. Intraoperative frozen pathology is not reliable, making careful intraoperative examination paramount. Surgical excision should include en bloc excision of the tumor, including the ipsilateral thyroid lobe and straps if involved. ^{37 , 38 , 39} Consideration should be given to primary level VI dissection if there is a concern for lymphadenopathy discovered at the time of surgery.

Parathyroid carcinoma carries a poor prognosis, with the 5-year survival reported as low as 49%. Interestingly, these patients usually die as a result of their uncontrolled hypercalcemia as opposed to local or metastatic disease. Harari et al ³⁸ reported a recurrence rate of 49 to 60% after surgical resection. This recurrence can be determined by monitoring serum calcium, parathyroid hormone, and carcinoembryonic antigen (CEA), with an increase being an ominous sign of recurrence.