The precise regulation of the serum ionized calcium concentration is necessary to sustain human life. The calcium cation is central to a myriad of reactions, from enzymatic function to the coagulation cascade to muscle fiber contraction and neurotransmission to the dynamic buildup and breakdown of the scaffolding that houses it all. The majority of calcium in the human body is found in the skeleton and comprises approximately 2% of the average individual’s body weight. Serum calcium levels are precisely maintained through an intricate interplay of checks and balances that begin and end with the parathyroid glands. The regulatory axis of calcium consists of the parathyroid glands, parathyroid hormone (PTH), membrane calcium receptors, the kidneys, the gut, and bone. Membrane calcium receptors on the cells of the parathyroid glands sense minute decreases in serum ionized calcium levels, triggering a cascade beginning with the secretion of PTH. This stimulates mobilization of calcium from bone, a reduction in renal calcium excretion, and an increase in renal hydroxylation of vitamin D, indirectly affecting calcium absorption in the duodenum and proximal jejunum. When calcium increases to within an acceptable range, calcium receptor-based stimulation of the parathyroids ceases, and secretion of PTH is inhibited. Thus, under normal conditions, the defining relationship between serum calcium and serum PTH is inverse: that is, high serum calcium begets low serum PTH and vice versa.

Diseases of the parathyroid are manifest almost exclusively as derangements in calcium metabolism. Hypercalcemia is the most common presentation, although the differential diagnosis of isolated hypercalcemia may be broad and complex. When hypercalcemia is associated with inappropriately high serum PTH, it is considered primary hyperparathyroidism (PHPT). This presupposes no antecedent renal disease, lithium therapy, or malabsorptive syndrome. In PHPT, the calcium level is generally high-normal to significantly elevated, and PTH levels are moderately elevated. PHPT may come in the form of single- or multigland adenoma, four-gland hyperplasia, or (rarely) parathyroid carcinoma.

Secondary hyperparathyroidism (SHPT) refers to the situation in which a derangement in calcium homeostasis (of a nonparathyroid cause) leads to a compensatory increase in PTH secretion. Unlike with PHPT, in SHPT, the elevation of serum PTH is an appropriate physiologic response to a perceived calcium deficit. The serum calcium level is generally in the low-normal range, and PTH is proportionately elevated. This is seen most often in the setting of end-stage renal disease (ESRD) (Figure 10-1) but may also result from other disorders of bone metabolism and the gastrointestinal (GI) tract.

On occasion, after prolonged secondary stimulation, the hyperfunctioning parathyroids are rendered unresponsive to serum calcium concentrations via a loss of calcium-sensing receptors, and they enter into an autonomous secretory state, or tertiary hyperparathyroidism (THPT). The serum calcium level is usually in the high-normal to high range, with a markedly pronounced elevation of PTH. Tertiary disease may occur after correction of the underlying defect in calcium metabolism, which is most often achieved through renal transplantation. Both SHPT and THPT involve uniform overstimulation of the glands and therefore manifest almost exclusively as four-gland hyperplasia.1 Histologically, whereas resected glands from patients with SHPT show either diffuse or nodular hyperplasia,2 those taken from patients with tertiary disease may be hyperplastic or even adenomatous.

The epidemiology of SHPT and THPT is best discussed within the context of the underlying process driving the disease. Most simply put, SHPT may occur in any individual with chronic hypocalcemia or chronic hyperphosphatemia. Chronic hypocalcemia may be the result of malnutrition, malabsorption, vitamin D deficiency, use of various drugs (including lithium), chronic cholestasis, and so on. Thus, three populations are generally at risk: patients with chronic kidney disease, patients with malabsorptive syndromes, and patients at the extremes of age. Overall, no racial predilection exists, and the incidence is equal in males and females, although racial and gender differences are thought to exist within certain subgroups of patients. THPT tends to occur in individuals exhibiting prolonged severe secondary disease.

SHPT occurs as a natural consequence of ESRD (see Figure 10-1), and the severity of derangement may only be ameliorated via aggressive medical management of calcium and phosphate metabolism. Approximately 65% to 75% of patients with renal failure have clinically apparent disease. Of these, only around 5% fail medical therapy, resulting in the need for surgical intervention. Of the patients with ESRD and SHPT who undergo transplantation, approximately 5% to 7% develop tertiary disease, requiring definitive surgical management.

Traditional discussions regarding SHPT and THPT focus primarily on disease resulting from progressive renal impairment because it is the most common cause of adult disease in the United States. However, with the increase of obesity surgery, the role of malabsorptive syndromes warrants mention here. The prevalence of SHPT in all individuals with malabsorptive syndrome remains somewhat ill-defined. However, as the number of patients undergoing surgery for obesity continues to climb, there is a growing number of patients in which a malabsorptive state has been intentionally induced, and this population is clearly at risk. Much of the recent literature suggests that the prevalence of SHPT in the gastric bypass population may be as high as 20% to 30%.3,4 The incidence of THPT in this group of patients appears to be negligible.

Similar to the epidemiology, the risk factors for SHPT and THPT relate to the underlying metabolic derangement. Risk factors for secondary disease include chronic renal failure (CRF), malnutrition (including rickets), malabsorption (celiac disease, surgical manipulation of the GI tract), cholestatic liver disease, advanced age (lack of sunlight, poor nutrition, renal dysfunction), some cancers, lithium therapy, and aluminum toxicity. Additional but unusual risk factors include oral contraceptive use and idiopathic hypercalciuria. Essentially, any condition that stimulates the parathyroid glands to increase production and secretion of PTH can be a risk factor for SHPT, especially if it is a sustained stimulus. Thus, technically speaking, SHPT is not a true endocrine disorder. The only identifiable risk factor for progression to THPT is the duration of SHPT.

Classically, patients with CRF-related SHPT experienced symptoms of bone pain, GI dysfunction, arthritis, myopathy, tendon rupture, pruritis, and extraskeletal calcifications. However, advances in the medical management of patients with renal failure together with earlier institution of medical therapy for those with metabolic derangements have rendered patients relatively asymptomatic until later in the disease course. Signs and symptoms are now relatively nonspecific and are usually predated by laboratory and radiologic evidence of disease. Despite a decrease in symptomatology, though, the impact of SHPT with respect to its effects on the skeleton, cardiovascular system, and integument must not be trivialized.