Primary hyperparathyroidism

Sporadic Primary Hyperparathyroidism

Primary HPT occurs at all ages but is most common in the sixth decade of life. It is three times more common in women than in men. When HPT affects children, it is likely to be a component of familial endocrinopathies such as the multiple endocrine neoplasia (MEN) syndromes type I and II or familial HPT. The incidence of HPT is approximately 4 per 100,000 per year. 2

The underlying pathophysiology of HPT is caused by excessive secretion of parathyroid hormone (PTH), which leads to increased bone resorption by osteoclasts, increased intestinal calcium absorption, and increased renal tubular calcium reabsorption. The consequent hypercalcemia is also often accompanied by low-normal or decreased serum phosphate levels because PTH inhibits proximal tubular phosphate reabsorption.

Most cases of HPT (80%) are discovered accidentally by automated blood sample analyzers that were initially introduced into clinical practice in the 1970s. These cases have minimal or no symptoms, and calcium levels are only mildly elevated (lower than 12 mg/dL). Patients with HPT can present with any of the clinical manifestations summarized in Table 1 , and this diagnosis needs to be considered especially in any patient presenting with kidney stones, bone disease, or hypercalcemic crisis.

Renal calculi are seen in 15% to 20% of patients with HPT and, conversely, about 5% of patients with renal calculi have HPT. Some of these patients may have calcium levels in the upper range of normal. Most calculi are composed of calcium oxalate and the main factor in pathogenesis is hypercalciuria. Although PTH stimulates calcium reabsorption in the distal tubule, the kidney is overwhelmed by the increase in the amount of filtered calcium resulting from increased serum calcium levels. Patients with increased vitamin D levels are more likely to have hypercalcemia and nephrolithiasis.

Classic bone disease of HPT manifests with brown tumors, osteitis fibrosa cystica, and subperiosteal resorption on the radial aspect of middle phalanges. These findings are present only in severe and long-standing disease, and today are seen rarely, usually when disease is caused by parathyroid carcinoma and in secondary or tertiary HPT is associated with chronic renal insufficiency. 3 Low bone mineral density is found in some patients with HPT, but it is unclear whether this occurs more often than in the normal population. Some studies have shown decreased bone mineral density in untreated cases 3 but others have not. 4 However, most studies have shown an increased risk for vertebral fractures in patients with HPT. Hip fractures were studied in a cohort of 1800 patients in Uppsala, Sweden, and revealed no extra risk for women but an increased risk in men. 5

Hypercalcemic crisis is a rare manifestation and is characterized by calcium levels usually above 15 mg/dL and severe symptoms of hypercalcemia, particularly central nervous system (CNS) dysfunction. Abdominal pain, pancreatitis, peptic ulcer disease, nausea, and vomiting are also seen more commonly in these patients. The mechanism whereby a crisis develops is not clear, but dehydration, intercurrent illness, and possibly infarction of parathyroid adenoma in some patients all play roles.

Several studies have found excessive mortality in patients with HPT, with most of the excess caused by cardiovascular disease. The largest study included 4461 patients and measured an increased mortality risk of 1.71 for men and 1.85 for women. 6
Diagnosis

The diagnosis of HPT requires an elevated serum calcium level, with simultaneous demonstration of elevated PTH levels (in 80% to 90% of patients) or within normal limits (in 10% to 20% of patients). Note that patients with hypercalcemia should have their PTH level suppressed and that the “normal” level is inappropriately high in these patients. The PTH elevated should be determined by an assay that measures the intact PTH molecule. The phosphorus level may be low but is usually just in the low-normal range. Urinary calcium excretion is measured by a 24-hour urine collection that should also specify total volume and urine creatinine levels; hypercalciuria should be considered if the urinary calcium level is higher than 400 mg/day. In addition, low calcium excretion (lower than 150 mg/day) may signify familial hypercalcemic hypocalciuria, which is not surgically treatable.

A careful family history is paramount for the recognition of familial forms of primary HPT. In these cases, urinary screening for catecholamine overproduction is important before surgical treatment.

Localization of abnormal parathyroid glands preoperatively by means of ultrasound, Tc 99m-sestamibi scintigraphy, or magnetic resonance imaging (MRI) may offer a possibility for a less invasive surgical approach. The accuracy of these radiologic modalities is variable. They are not required for the diagnosis of HPT, but serve mainly as guides for surgical strategy, and the selection of these tests should be left to the surgeon.
Treatment
Indications for Treatment.

Removal of the abnormal and hyperfunctioning parathyroid tissue results in a long-term cure of HPT in 96% of patients and significant improvement in associated symptoms. The following criteria were proposed as indications for parathyroidectomy based on a National Institutes of Health–sponsored panel and endocrine specialty societies: 7

Serum Ca level more than 1 mg/dL above the upper limit of normal
Marked hypercalciuria higher than 400 mg/day
Creatinine clearance reduced more than 30% compared with age-matched controls
Reduction in bone mineral density of the femoral neck, lumbar spine, or distal radius of more than 2.5 standard deviations below peak bone mass (T score lower than -2.5)
Age younger than 50 years
Patients for whom medical surveillance is not desirable or possible
Presence of any complications (e.g., nephrolithiasis, overt bone disease)
An episode of hypercalcemic crisis

However, because no effective medical therapy for HPT exists, all patients with HPT who are otherwise healthy for surgery should be referred for surgical treatment.
Surgical Treatment.

Parathyroid surgery remains the single most effective treatment option in HPT and requires removal of all abnormal parathyroid tissue. Traditionally, in the vast majority of U.S. practices, this has meant bilateral exploration of the neck to identify all (typically four) parathyroids, assess which ones are abnormal, and remove only the abnormal glands. The setting of multiglandular hyperplasia requires subtotal parathyroidectomy or total parathyroidectomy, with reimplantation of parathyroid tissue into the sternocleidomastoid or forearm muscles. The parathyroids may then also be cryopreserved as a safeguard against future hypocalcemia, in which case the patient may undergo autotransplantation of autogenous, stored parathyroid tissue. In experienced hands, this approach has an exceptional rate of successful long-term cure of HPT (more than 96%) and a low rate of surgical complications (hypocalcemia less than 1%, recurrent laryngeal nerve injury 2% to 5%, neck hematoma or infection less than 1%). 8

In recent years, parathyroid procedures have been developed using smaller incisions under sedation and local anesthesia, and with the opportunity for outpatient surgery. Minimally invasive parathyroid surgery has become more frequently requested by patients and primary care physicians alike, even though it does not represent a uniform set of techniques. Depending on regional practices, minimally invasive parathyroid surgery can include laparoscopic, radio-guided or, most frequently, only unilateral neck surgery. The success of these approaches in curing HPT and minimizing complications is relatively unknown because clinical follow-up periods are still short. Minimally invasive parathyroid surgery is appropriate only for patients who have a single, clearly defined parathyroid abnormality on ultrasound, sestamibi scan, or both and when parathyroid hormone levels can be monitored intraoperatively. Bilateral neck exploration is mandatory in all other cases and for patients with familial or genetic syndromes.
Medical Treatment.

Patients who are not treated surgically should be managed to ensure good hydration and to avoid thiazide diuretics. Ambulation should be encouraged. Calcium intake should be average, because excessive intake may aggravate hypercalcemia, especially in patients with high calcitriol levels, whereas low calcium intake may stimulate PTH secretion. Bisphosphonates may be used to lower the serum calcium level in patients with symptomatic hypercalcemia (see later, “Treatment of Hypocalcemia”), although they are usually not effective.
Familial Forms of Hyperparathyroidism

Up to 10% of cases of primary HPT are hereditary forms. Recognition is important because management of many patients and their families may be affected.

The most common familial form is multiple endocrine neoplasia syndrome type I (MEN-I). In this disorder, primary HPT is almost invariably present (in more than 95% of patients) by the age of 65 years, but may be diagnosed in children and even in infants. Indications for surgical intervention are generally the same as for sporadic cases. Pancreatic tumors are present in 30% to 80% of patients. These are usually islet cell tumors secreting gastrin and causing Zollinger-Ellison syndrome in about two thirds of cases. The second most common pancreatic tumor is insulinoma. Tumors secreting various substances have been described.

Pituitary adenomas affect 15% to 50% of patients and are mostly prolactinomas, although tumors causing acromegaly and Cushing’s disease also occur. Adrenocortical hyperplasia is seen in about one third of patients.

MEN-I is caused by autosomal dominant mutation of the menin gene on chromosome 11. Genetic testing is cumbersome, and screening of family members should be done by determining serum calcium levels. Some patients develop MEN-1–associated lesions as late as age 35 years.

MEN-II is characterized by the development of medullary thyroid carcinoma, which occurs in almost all patients. Hyperparathyroidism occurs in about one half of affected individuals; most are asymptomatic. Pheochromocytoma or adrenal medullary hyperplasia is an associated feature. The mutated gene is the RET protooncogene. Genetic testing of family members is desirable because it clearly identifies individuals at risk, and timely thyroidectomy is lifesaving.

Other familial syndromes are rare and include the HPT–jaw tumor syndrome and familial isolated primary HPT.