Medullary Carcinoma of the Thyroid
MCT, a neoplasm of thyroidal C cells, accounts for 5% to 10% of all thyroid malignancies. Approximately 75% of MCTs are sporadic. The remainder is familial and associated with one of three heritable syndromes: familial isolated MCT; multiple endocrine neoplasia 2A (MEN 2A), consisting of MCT, pheochromocytoma, and primary hyperparathyroidism; or multiple endocrine neoplasia 2B (MEN 2B), consisting of MCT, pheochromocytoma, multiple mucosal neuromas, and, rarely, primary hyperparathyroidism (Table 8–4). The MEN syndromes are more extensively discussed in Chapter 22.
Table 8–4 Clinical Presentations Resulting from RET Mutations. ||Download (.pdf)
Table 8–4 Clinical Presentations Resulting from RET Mutations.
|MEN 2A||MCT, pheochromocytoma, primary hyperparathyroidism|
|MEN 2A with lichen amyloidosis||MEN 2A + pruritic lesions of upper back|
|MEN 2A or Familial MCT and Hirschsprung disease||MCT, Hirschsprung disease|
|MEN 2B||MCT, pheochromocytoma, marfanoid habitus, intestinal and mucosal ganglioneuromatosis|
Understanding the pathogenesis of MCT has been greatly enhanced by the identification of causative mutations in the RET proto-oncogene located on chromosome 10q11.2. The RET gene encodes a membrane tyrosine kinase receptor whose ligands belong to the glial cell line-derived neurotrophic factor (GDNF) family. This receptor is expressed developmentally in migrating neural crest cells that give rise to hormone-secreting neuroendocrine cells (eg, C cells and adrenal medullary cells) and to the parasympathetic and sympathetic ganglia of the peripheral nervous system. Remarkably, different mutations in RET can produce five distinct diseases (see Table 8–4). Inheritance of certain activating mutations is responsible for MEN 2A and familial MCT. Inheritance of a different set of activating mutations causes MEN 2B. In over half of sporadic MCTs, the tumor has a clonal somatic mutation (present in the tumor but not in genomic DNA), which is identical to one of the mutations that is responsible for the familial forms of MCT. These somatic mutations clearly play a causative role in sporadic MCT. Mutations in the RET gene can also produce Hirschsprung disease, a congenital absence of the enteric parasympathetic ganglia, that can lead to a disturbance in intestinal motility, resulting in megacolon.
MCT is usually located in the middle or upper portions of the thyroid lobes. It is typically unilateral in sporadic cases but often multicentric and bilateral in familial forms of the disease. The natural history of MCT is variable. Sporadic tumors may be quite aggressive or very indolent; the mean 5-year survival rate is about 50%. The behavior of familial forms varies among syndromes. MEN 2B has the most aggressive form of MCT, with a 2-year survival of about 50%; MEN 2A has a course similar to that of sporadic forms of this tumor, and familial MCT has the most indolent course of all MCT. The natural history of the tumor in familial MCT, MEN 2A, and MEN 2B syndromes has been dramatically impacted by early prophylactic total thyroidectomy that is now advised in most carriers of disease-causing RET mutations. MCT may spread to regional lymph nodes or undergo hematogenous spread to the lungs and other viscera. When metastatic, this tumor is sometimes associated with a chronic diarrhea syndrome. The pathogenesis of the diarrhea is unclear. In addition to CT, these tumors secrete a variety of other bioactive products, including prostaglandins, serotonin, histamine, and peptide hormones (ACTH, somatostatin, corticotropin-releasing hormone). In some cases, the associated diarrhea responds dramatically to treatment with long-acting somatostatin analog such as octreotide, which blocks secretion of these bioactive products.
CT is a tumor marker for MCT. It is most sensitive for this purpose when secretion is stimulated with provocative agents. The standard provocative tests use pentagastrin (0.5 ug/kg intravenously over 5 seconds) or a rapid infusion of calcium gluconate (2 mg calcium/kg over 1 minute). Blood samples are obtained at baseline and 1, 2, and 5 minutes after the stimulus. For maximal sensitivity, both tests are usually combined, with the calcium infusion immediately followed by administration of pentagastrin. Although basal CT levels are often normal in early tumors, CT levels may be many times higher than normal in patients with disseminated MCT. Despite this, the patients are uniformly normocalcemic. Although tumors secrete larger molecular weight forms of CT with decreased biologic activity, monomeric CT levels are often high as well. RET oncogene analysis has replaced provocative testing in most cases, although basal CT levels are still used to follow disease burden postoperatively and during chemotherapy trials.
Members of families carrying RET mutations must be screened for MCT and, if positive, for the associated tumors that occur in MEN 2A and MEN 2B (see Table 8–4 and Chapter 22). In the case of MCT, the presence of the RET mutation in an individual generally leads to the recommendation for a total thyroidectomy prior to the development of frank malignancy or abnormal CT levels. It is recommended in a kindred with a known RET mutation that children be screened at birth for the carrier state. Total thyroidectomy with or without central compartment lymph node dissection can be performed in mutation carriers, and further testing can be discontinued in genetically normal family members. The timing of prophylactic thyroidectomy in carriers of RET mutations, however, depends on the genotype present (ie, codon mutated in RET) (Table 8–5). As supported by the genotype-phenotype correlations in these diseases, surgery is recommended in certain high-risk cases before 1 year of age, in cases of intermediate risk before 5 years of age, and in lower-risk patients later in childhood usually by 10 years of age. Because a limited number of mutations in RET cause more than 95% of hereditary MCT and up to 25% of sporadic disease, it is possible to screen the majority of patients using commercial reference laboratories.
Table 8–5 RET Mutations: Their Frequency and Age at Which Surgery Is Recommended in Gene Carriers Based on Level of Risk of MCT. ||Download (.pdf)
Table 8–5 RET Mutations: Their Frequency and Age at Which Surgery Is Recommended in Gene Carriers Based on Level of Risk of MCT.
|Codon||Frequency (Percent of Total)|
|790, 791, 891||Uncertain|
Apparent sporadic MCT also calls for genetic testing and family studies. Up to 25% of new cases of MCT may actually be probands of families who harbor one of the familial syndromes. It has been noted in some kindreds after careful and lengthy follow-up that some individuals develop pheochromocytomas or primary hyperparathyroidism. Therefore, patients with apparent familial MCT should be followed indefinitely for one of these components of MEN 2A. Screening of family members can be accomplished by genetic testing, once the index case is identified. Identification of a mutation that is present only in tumor tissue would establish the mutation as somatic and the tumor as a sporadic one. Identification of the same RET mutation in tumor and genomic DNA would make the diagnosis of a familial form of the disorder and would mandate careful screening of the family.
A number of symptoms and signs accompany hypercalcemia. They include central nervous system effects such as lethargy, depression, psychosis, ataxia, stupor, and coma; neuromuscular effects such as weakness, proximal myopathy, and hypertonia; cardiovascular effects such as hypertension, bradycardia (and eventually asystole), and a shortened QT interval; renal effects such as stones, decreased glomerular filtration, polyuria, hyperchloremic acidosis, and nephrocalcinosis; gastrointestinal effects such as nausea, vomiting, constipation, and anorexia; eye findings such as band keratopathy; and systemic metastatic calcification. Primary hyperparathyroidism, one of the most common etiologies for hypercalcemia, has the mnemonic for recalling its signs and symptoms as stones, bones, abdominal groans, and psychic moans (Figure 8–12).
Signs and symptoms of primary hyperparathyroidism.
Although many disorders are associated with hypercalcemia (Table 8–6), they produce it by a limited number of mechanisms: (1) increased bone resorption, (2) increased gastrointestinal absorption of calcium, or (3) decreased renal excretion of calcium. Although any of these mechanisms can be involved in a given patient, the common feature of virtually all hypercalcemic disorders is accelerated bone resorption. The only hypercalcemic disorder in which bone resorption does not play a part is the milk-alkali syndrome.
Table 8–6 Causes of Hypercalcemia. ||Download (.pdf)
Table 8–6 Causes of Hypercalcemia.
Associated with MEN 1 or MEN 2A
Variant forms of hyperparathyroidism
Familial benign hypocalciuric hypercalcemia
Tertiary hyperparathyroidism in chronic renal failure
Humoral hypercalcemia of malignancy
Caused by PTHrP (solid tumors, adult T-cell leukemia syndrome)
Caused by 1,25(OH)2D (lymphomas)
Caused by ectopic secretion of PTH (rare)
Local osteolytic hypercalcemia (multiple myeloma, leukemia, lymphoma)
|Sarcoidosis or other granulomatous diseases|
Vitamin A intoxication
Vitamin D intoxication
Estrogens, androgens, tamoxifen (in breast carcinoma)
|Acute renal failure|
|Idiopathic hypercalcemia of infancy|
|Serum protein disorders|
The central feature of the defense against hypercalcemia is suppression of PTH secretion. This reduces bone resorption, renal production of 1,25(OH)2D, and, thereby, intestinal calcium absorption and increases urinary calcium losses. The kidney plays a key role in the adaptive response to hypercalcemia as the only route of net calcium elimination. The level of renal calcium excretion is markedly increased by the combined effects of an increased filtered load of calcium and the suppression of PTH. However, the patient who relies on the kidneys to excrete an increased calcium load is in precarious balance. Glomerular filtration is impaired by hypercalcemia; the urinary concentrating ability is diminished, predisposing to dehydration; poor mentation may interfere with access to fluids; and nausea and vomiting may further predispose to dehydration and renal azotemia. Renal insufficiency, in turn, compromises calcium clearance, leading to a downward spiral (Figure 8–13). Thus, once established, many hypercalcemic states are self-perpetuating or aggravated through the vicious cycle of hypercalcemia. The only alternative to the renal route for elimination of calcium from the extracellular fluid is deposition of calcium phosphate and other salts in bone and soft tissues. Soft tissue calcification is observed with massive calcium loads, with massive phosphate loads (as in tumor lysis syndrome, crush injuries and compartment syndromes), and when renal function is markedly impaired and the calcium-phosphate product rises.
Vicious cycle of hypercalcemia. Once established, hypercalcemia can be maintained or aggravated as depicted. (Reproduced, with permission, from Felig P, Baxter JD, Frohman LA, ed. Endocrinology and Metabolism. 3rd ed. McGraw-Hill; 1995.)
As a practical matter, the categories for differential diagnosis are primary hyperparathyroidism and everything else (see Table 8–6). Hyperparathyroidism is by far the most common cause of hypercalcemia and has distinctive pathophysiologic features. Thus, the first step in the differential diagnosis is determination of intact PTH (Figure 8–14). If the PTH level is high, and thus inappropriate for hypercalcemia, little further workup is required except to consider the variant forms of hyperparathyroidism that are discussed later. If the PTH level is suppressed, then a search for other entities must be conducted. Most other entities in Table 8–6 are readily diagnosed by their distinctive features, as discussed later.
Clinical utility of immunoradiometric assay for intact PTH. (Reproduced, with permission, from Endres DB, et al. Measurement of parathyroid hormone. Endocrinol Metab Clin North Am. 1989;18:611.)
Disorders Causing Hypercalcemia
Primary hyperparathyroidism results from the excessive secretion of PTH and typically produces frank hypercalcemia. With the advent of multiphasic screening of serum chemistries, we have come to recognize that primary hyperparathyroidism is a common and usually asymptomatic disorder. Its incidence is approximately 42 per 100,000, and its prevalence is up to 4 per 1000 in women over age 60. Primary hyperparathyroidism is approximately 2 to 3 times more common in women than in men.
Etiology and Pathogenesis
Primary hyperparathyroidism is caused by a single parathyroid adenoma in about 80% of cases and by primary hyperplasia of the parathyroids in 10% to 15%. Parathyroid carcinoma is a rare cause of hyperparathyroidism, accounting for 1% to 2% of cases. Parathyroid carcinoma is often recognizable preoperatively because it presents with severe hypercalcemia or a palpable neck mass.
Sporadic parathyroid adenomas have a clonal origin, indicating that they can be traced back to an oncogenic mutation in a single progenitor cell. A few of these genetic alterations have been identified and/or assigned to chromosomal loci. About 25% of sporadic parathyroid adenomas have chromosomal deletions involving chromosome 11q12-13 that are thought to eliminate the putative tumor suppressor gene MENIN. As reviewed later and in Chapter 22, loss of the functioning menin protein, a tumor suppressor, is the cause of parathyroid, pituitary, and pancreatic tumors in the MEN 1 syndrome. An additional 40% of parathyroid adenomas display allelic loss on chromosome 1p (1p32pter).
Another important locus on chromosome 11 that has been implicated in approximately 4% of sporadic parathyroid adenomas involves the cyclin D1 gene. In the initial elucidation of this pathogenic mechanism, a chromosomal rearrangement was found in a parathyroid tumor. Breakage and then inversion of a piece of chromosome 11 led to the expression of cyclin D1, a cell-cycle regulatory protein, under the control of the PTH promoter. As expected, this promoter is highly active in parathyroid cells, resulting in marked overexpression of cyclin D1 in these tumor cells. Cyclin D1 is normally expressed at high levels in the G1 phase of the cell cycle and permits entry of cells into the mitotic phase of the cycle. Thus, a parathyroid-specific disorder of cell-cycle regulation leads to abnormal cell proliferation and ultimately excessive PTH production.
Parathyroid hyperplasia accounts for 12% to 15% of cases of primary hyperparathyroidism and is the pathologic basis for these inherited conditions: MEN 1, MEN 2A, the hyperparathyroidism-jaw tumor (HPT-JT) syndromes, and isolated familial hyperparathyroidism. In all of these instances four or fewer glands may be involved at the time of presentation. Inheritance of all of these conditions is autosomal dominant.
Parathyroid hyperplasia was traditionally viewed as an example of true hyperplasia, a polyclonal expansion of cell mass. This occurs in other endocrine tissues when a trophic hormone present in excess (eg, ACTH excess) induces bilateral adrenal hyperplasia. Molecular analysis, however, has revised this view. Parathyroid hyperplasia appears to share similar pathogenic mechanisms with parathyroid adenomas. The MEN 1 syndrome illustrates this. MEN 1 is due to the inherited inactivation of one allele of the MENIN gene, which encodes a tumor suppressor. Acquired postnatal somatic mutations in the remaining MENIN gene result in loss of the other allele's function. This leads to tumors in those endocrine tissues in which the gene is expressed. In this view, multicentric somatic mutations would account for the occurrence of four-gland hyperparathyroidism.
Kindreds with a presentation like MEN 1 but without mutations in MENIN have been investigated for germline mutations in cyclin-dependent kinase inhibitors (CDKIs) of which there are seven known genes. In an analysis of 196 consecutive cases of MEN 1 or other tumor states without germline mutations in MENIN, one laboratory found seven probable pathologic mutations in these genes. Three of the seven mutations were in p27 with the remainder in three other CDKIs (p15, p18, and p27). These mutations are thought to be disease causing because abnormalities in CDKI–protein interaction were uncovered in the majority of these mutations tested. The CDKIs negatively control the cell cycle through interaction with and inhibition of cyclins D, E, and A. The germline mutations in these kindreds would, therefore, involve loss of function in known inhibitors of cell growth and cell cycle activity.
In MEN 2A, the occurrence of parathyroid hyperplasia is also a consequence of expression of activating mutations of the RET gene in the four glands. These and other studies clearly indicate that parathyroid hyperplasia is typically monoclonal in its origin, implying that cell hyperproliferation arose from a single progenitor cell in each gland.
In addition to hyperparathyroidism, as one part of classical MEN 1, it is now clear that a subset of cases of familial isolated hyperparathyroidism is due to germline mutations in the MENIN gene. This observation established the concept that isolated familial hyperparathyroidism can be an allelic variant of the MEN 1 syndrome. The variation from MEN 1 lies in the absence of tumors in the other endocrine glands.
Other cases of familial isolated hyperparathyroidism are explained, albeit rarely, by mutations in the gene that causes the HPT-JT syndrome (see later). Additional families with isolated hyperparathyroidism have, as yet, no identified mutations.
In contrast to MEN 1 and MEN 2A, both benign and malignant parathyroid tumors occur in the HPT-JT syndrome. This is an autosomal dominant disorder that includes primary hyperparathyroidism (90%), jaw tumors (ossifying fibromas of the mandible or maxilla) (30%), renal cysts (10%), and less frequently renal hamartomas and Wilms tumor. Linkage analysis originally determined the locus for this syndrome, which had been designated as hyperparathyroidism 2 or HRPT2 to be at 1q24-q32. Inactivating mutations in HRPT2 gene, encoding the protein parafibromin, have been identified in HPT-JT kindreds. Mutations in the HRPT2 gene inactivate parafibromin. This protein like menin normally functions as a tumor suppressor. Its function(s) in parathyroid cells have not yet been elucidated.
Inactivating mutations in the HRPT2 gene have also been identified in kindreds with isolated familial hyperparathyroidism. Both single- and multiple-gland disease have been noted. It was further noted that approximately 15% of affected individuals with HPT-JT syndrome develop parathyroid cancer, instead of adenomas or hyperplasia, suggesting that reduced parafibromin function also contributes to a malignant phenotype. Several groups have shown that a large percentage (~70%) of patients with sporadic parathyroid cancer harbor somatic mutations in the HRPT2 gene. Surprisingly, approximately 30% of individuals with isolated parathyroid cancer have also been found to have germline mutations in HRPT2 without the other manifestations of the HPT-JT syndrome. It is now thought that the majority of sporadically occurring parathyroid cancers are due to somatic mutations in the coding region of the HRPT2 gene. It is anticipated that mutations in the noncoding regulatory regions of this gene may explain additional cases. A pathologic study of more than 50 cases of parathyroid cancer indicates that the loss of parafibromin immunoreactivity is a specific and key feature of malignancy with a sensitivity of 96% (CI, 85%-99%) and specificity of 99% (CI, 92%-100%).
The typical clinical presentation of primary hyperparathyroidism has evolved considerably over the past few decades. As the disease continues to be detected primarily by multiphasic screening that includes determination of serum calcium levels, there has been a marked reduction in the frequency of the classic signs and symptoms of primary hyperparathyroidism. Renal disease (stones, decreased renal function, and occasionally nephrocalcinosis) and the classic hyperparathyroid bone disease osteitis fibrosa cystica are decidedly rare today. In fact, about 85% of patients presenting today have neither bone nor renal manifestations of hyperparathyroidism and are regarded as asymptomatic or at most minimally symptomatic. At the same time, we have begun to recognize more subtle manifestations of hyperparathyroidism. This has presented a number of questions about the role of parathyroid surgery in primary hyperparathyroidism, which are discussed later (see Treatment).
Hyperparathyroid bone disease—The classic bone disease of hyperparathyroidism is osteitis fibrosa cystica. Formerly common, this disorder now occurs in less than 10% of patients. Clinically, osteitis fibrosa cystica causes bone pain and sometimes pathologic fractures. The most common laboratory finding is an elevation of the alkaline phosphatase level, reflecting high bone turnover. Histologically, there is an increase in the number of bone-resorbing osteoclasts, marrow fibrosis, and cystic lesions that may contain fibrous tissue (brown tumors). The most sensitive and specific radiologic finding of osteitis fibrosa cystica is subperiosteal resorption of cortical bone, best seen in high-resolution films of the phalanges (Figure 8–15A). A similar process in the skull leads to a salt-and-pepper appearance (Figure 8–15B). Bone cysts or brown tumors may present as osteolytic lesions. Dental films may disclose loss of the lamina dura of the teeth, but this is a nonspecific finding also seen in periodontal disease.
The other important skeletal consequence of hyperparathyroidism is osteoporosis. Unlike other osteoporotic disorders, hyperparathyroidism often results in the preferential loss of cortical bone (Figure 8–16). In general, both the mass and mechanical strength of trabecular bone are relatively maintained in mild primary hyperparathyroidism. Patients who are followed medically with this disease generally do not experience progressive bone loss for as long as 8 years after diagnosis (Figure 8–17). This may be due to the fact that mild PTH excess has an anabolic effect on the skeleton to maintain or even increase bone mass. Although osteoporosis, defined by bone mineral density (BMD) T-scores by dual-energy x-ray absorptiometry (DXA) of −2.5 or lower, is generally considered to be an indication for surgical treatment of primary hyperparathyroidism, the impact of low bone mass on morbidity is difficult to corroborate clinically (see Treatment of Hypercalcemia).
Hyperparathyroid kidney disease—Once common in primary hyperparathyroidism, kidney stones now occur in 10% to 20% of cases depending on the series. These are usually calcium oxalate stones. From the perspective of a stone clinic, only about 7% of calcium stone formers prove to have primary hyperparathyroidism. They are difficult to manage medically, and stones constitute one of the agreed indications for parathyroidectomy. Clinically evident nephrocalcinosis rarely occurs, but a gradual loss of renal function is not uncommon. Renal function is stabilized after a successful parathyroidectomy, and otherwise unexplained renal insufficiency (defined as an estimated glomerular filtration rate [eGFR] <60 mL/min) in the setting of primary hyperparathyroidism is also considered to be an indication for surgery because of the risk of progression. Chronic hypercalcemia can also compromise the renal concentrating ability, giving rise to polydipsia and polyuria.
Nonspecific features of primary hyperparathyroidism—Although stupor and coma occur in severe hypercalcemia, the degree to which milder impairments of central nervous system function affect the typical patient with primary hyperparathyroidism is unclear. Lethargy, fatigue, depression, difficulty in concentrating, and personality changes may occur; however, some patients appear to benefit from parathyroidectomy. Frank psychosis also responds to surgery on occasion. Muscle weakness with characteristic electromyographic changes is also seen, and there is evidence from controlled clinical trials that surgery can improve muscle strength. A number of studies have examined quality of life (QOL) and psychological function in patients with primary hyperparathyroidism pre- and post-parathyroid surgery, compared to a medically followed group. Results vary as to whether QOL improves with surgery. It was formerly thought that the incidence of hypertension was increased in primary hyperparathyroidism, but more recent evidence suggests that it is probably no greater than in age-matched controls, and parathyroidectomy appears to be of no benefit. Dyspepsia, nausea, and constipation all occur, probably as a consequence of hypercalcemia, but there is probably no increase in the incidence of peptic ulcer disease. The articular manifestations of primary hyperparathyroidism include chondrocalcinosis in up to 5% of patients. Acute attacks of pseudogout, however, are less frequent.
A: Magnified x-ray of index finger on fine-grain industrial film showing classic subperiosteal resorption in a patient with severe primary hyperparathyroidism. Note the left (radial) surface of the distal phalanx, where the cortex is almost completely resorbed, leaving only fine wisps of cortical bone. B: Skull x-ray from a patient with severe secondary hyperparathyroidism due to end-stage renal disease. Extensive areas of demineralization alternate with areas of increased bone density, resulting in the “salt and pepper” skull x-ray. (Both films courtesy of Dr. Harry Genant.)
Bone mineral density at several sites in primary hyperparathyroidism shown as the percentage of expected for age.
(Reproduced, with permission, from Silverberg SJ, et al. Nephrolithiasis and bone involvement in primary hyperparathyroidism. Am J Med. 1990;89:327.)
Mean changes in bone mineral density (BMD) measurements by dual-energy x-ray absorptiometry (DXA) in patients who underwent parathyroidectomy compared with medical follow-up during a 15-year observational study. BMD changes are reported compared with baseline and were statistically different from baseline as shown (*P <.05, **P <.01, ***P < 0.001). The number of patients whose measurements are included are shown underneath each time point. Either just before (distal 1/3 radius) or after 10 years of conservative follow-up (femoral neck) BMD measurements began to fall significantly, while lumbar spine BMD remained unchanged (Panel A). Patients who underwent parathyroidectomy demonstrated improved BMD which persisted during 15 years of follow-up (Panel B). (Reproduced and modified, with permission, from Rubin MR, et al. The natural history of primary hyperparathyroidism with or without parathyroid surgery after 15 years. J Clin Endocrinol Metab. 2008;93:3462. Copyright 2008 by The Endocrine Society. All rights reserved.)
Hypercalcemia is virtually universal in primary hyperparathyroidism, although the serum calcium sometimes fluctuates into the upper normal range. In patients with subtle hyperparathyroidism, repeated serum calcium measurements over a period of time may be required to establish the pattern of intermittent hypercalcemia. Both total and ionized calcium are elevated, and in most clinical instances there is no advantage to measuring the ionized calcium level. Patients with normocalcemic primary hyperparathyroidism, in whom subtle vitamin D deficiency and malabsorption have been eliminated, are being recognized more frequently. In patients with primary hyperparathyroidism, the serum phosphorus level is low-normal (<3.5 mg/dL) or low (<2.5 mg/dL) because of the phosphaturic effect of PTH. A mild hyperchloremic metabolic acidosis may also manifest itself.
The diagnosis of primary hyperparathyroidism in a hypercalcemic patient can be made by determining the intact PTH level. As shown in Figure 8–14, an elevated or even upper-normal level of PTH is clearly inappropriate in a hypercalcemic patient and establishes the diagnosis of hyperparathyroidism or one of its variants—FBHH or lithium-induced hypercalcemia. The reliability of the two-site intact PTH assay allows for the definitive diagnosis of primary hyperparathyroidism. In a patient with a high PTH level, there is no need to screen for such disorders as metastatic cancer or sarcoidosis. Determinations of BMD, renal function, and a plain abdominal radiograph for renal stones are often obtained for clinical decision-making reasons. A determination of urinary calcium concentration and urinary creatinine excretion should always be obtained to exclude FBHH.
The definitive treatment of primary hyperparathyroidism is parathyroidectomy. The surgical strategy (ie, minimally invasive vs bilateral neck exploration) depends on the ability of localizing studies such as sestamibi scanning to identify one clearly abnormal gland and the availability of intraoperative PTH determinations to verify that the disease-producing lesion has been removed during surgery. If multiple enlarged glands are suspected, the likely diagnosis is parathyroid hyperplasia or double adenoma. In patients with hyperplasia, the preferred operation is a 3½ gland parathyroidectomy, leaving a remnant sufficient to prevent hypocalcemia. Double parathyroid adenomas are both removed in affected patients. The pathologist is of little help in distinguishing among normal tissue, parathyroid adenoma, and parathyroid hyperplasia: these in essence are surgical diagnoses, based on the size and appearance of the glands. The recurrence rate of hypercalcemia is high in patients who have parathyroid hyperplasia—particularly in those with MEN 1 or allelic variants of MEN 1 or the HPT-JT syndromes, because of the inherited propensity for tumor growth. In such cases, the parathyroid remnant can be removed from the neck and implanted in pieces in forearm muscles to allow for easy subsequent removal of some parathyroid tissue if hypercalcemia recurs.
In experienced hands, the cure rate for a single parathyroid adenoma is more than 95%. The success rate in primary parathyroid hyperplasia is somewhat lower, because of missed glands and recurrent hyperparathyroidism in patients with MEN syndromes. There is a 20% incidence of persistent or recurrent hypercalcemia. However, parathyroidectomy is difficult surgery: the normal parathyroid gland weighs only about 40 mg and may be located throughout the neck or upper mediastinum. It is mandatory in this situation not only to locate a parathyroid adenoma, but also to find the other gland or glands and determine whether or not they are normal in size. Complications of surgery include damage to the recurrent laryngeal nerve, which passes close to the posterior thyroid capsule, and inadvertent removal or devitalization of all parathyroid tissue, producing permanent hypoparathyroidism. In skilled hands, the incidence of these complications is less than 1%. It is critical that parathyroid surgery be performed by someone with specialized skill and experience (see Chapter 26).
Localization studies of the parathyroid glands in patients with primary hyperparathyroidism and intraoperative PTH testing are critical components in the contemporary surgical management of patients presenting for minimally invasive surgical procedures. If localizing studies clearly indicate a single abnormal gland and if intraoperative PTH testing is available, surgical management generally consists of unilateral exploration with the removal of the single abnormal gland. Localization studies continue to be essential in the management of patients with recurrent or persistent hyperparathyroidism. The most successful procedures are 99</sp>mTc-sestamibi scanning, computed tomography, magnetic resonance imaging, and ultrasound. Individually, each has a sensitivity of 60% to 80% in experienced hands. Used in combination, they are successful in at least 80% of reoperated cases. Invasive studies, such as angiography and venous sampling, are reserved for the most difficult cases.
There is no definitive medical therapy for primary hyperparathyroidism. In postmenopausal women, estrogen therapy in high doses (1.25 mg of conjugated estrogens or 30-50 μg of ethinyl estradiol) produces an average decrease of 0.5 to 1 mg/dL in the serum calcium and an increase in BMD. The effects of estrogen are on the skeletal responses to PTH. PTH levels do not fall. Small series of patients provide experience with oral bisphosphonates (eg, alendronate) and the selective estrogen response modulator (SERM) raloxifene in these patients. Treatment with alendronate for 1 or 2 years reduces biochemical markers of bone turnover and improves BMD by DXA, especially in the spine and also in the femoral neck, compared to baseline values prior to treatment. Studies have shown that raloxifene, administered over several weeks, to postmenopausal women with mild primary hyperparathyroidism also reduces bone turnover markers significantly. Neither alendronate nor raloxifene have significant and or persistent effects on serum calcium or intact PTH levels, nor is either agent approved for treatment of primary hyperparathyroidism by the U.S. Food and Drug Administration (FDA). Calcimimetic agents that activate the parathyroid CaSR, currently under investigation, may offer an alternative to surgery. The calcimimetic cinacalcet is FDA-approved for the management of secondary hyperparathyroidism in patients on dialysis (see later). In small clinical trials, cinacalcet was shown to normalize serum [Ca2+] and raise serum phosphate with modest lowering of PTH levels in patients with mild asymptomatic primary hyperparathyroidism for up to 5 years of therapy. No significant changes in BMD by DXA were seen. This therapy, therefore, is most effective at controlling hypercalcemia in these patients.
The relatively asymptomatic status of most patients with primary hyperparathyroidism today presents a dilemma. Which of them should be subjected to surgery? To answer this question definitively, it is necessary to know more about the natural history of untreated primary hyperparathyroidism. Most observational studies lack long-term follow-up and appropriate control groups. However, one observational study of 15 years duration showed modest increases in serum [Ca2+] (after 10 years) and slow but consistent downward trends in BMD at cortical sites (femoral neck and distal radius) (after 8-10 years of follow-up) (see Figure 8–17A). This study has challenged the skeletal safety of long-term observation of otherwise asymptomatic patients. On the other hand, surgery is usually curative. In experienced hands, surgery has a low morbidity rate. Although parathyroid surgery has a substantial initial cost, over the long term, the cost-benefit ratio may be favorable when compared with a lifetime of medical follow-up. Moreover, there is a marked improvement in BMD after surgery (see Figure 8–17B), with sustained increases over 15 years postoperatively. Consensus Development Conferences or International Workshops in 1990, 2002, and 2008 examined evidence and published recommendations for surgery in mild asymptomatic primary hyperparathyroidism and for conservative management. Current recommendations are for surgery (1) if the serum calcium is greater than 1 mg/dL above the upper limits of normal; (2) if there had been a previous episode of life-threatening hypercalcemia; (3) if the eGFR is <60 mL/min; (4) if a kidney stone is present; (5) if the BMD by DXA at the lumbar spine, hip, or distal radius is substantially reduced (≥2.5 SD below peak bone mass; T-score ≤−2.5); (6) if the patient is young (<50 years of age); or (7) if long-term medical surveillance is not desired or possible. Patients with a coexisting illness complicating the management of hypercalcemia should also be referred for surgery.
The expert panel also considered neuropsychiatric dysfunction, impending onset of menopause, older age and functional status, biochemical markers of bone turnover, and nonclassical symptoms of primary hyperparathyroidism (eg, gastrointestinal and cardiovascular manifestations) in their recommendations. The participants thought that there was sufficient uncertainty regarding these factors that firm recommendations for surgical referral based on these factors alone was not warranted. This panel agreed, however, that these clinical issues should be carefully considered in making decisions regarding surgery and/or long-term follow-up in individual patients.
Variants of Primary Hyperparathyroidism
Familial Benign Hypocalciuric Hypercalcemia
Inherited as an autosomal dominant trait, this disorder is responsible for lifelong asymptomatic hypercalcemia, first detectable in cord blood. Hypercalcemia is usually mild (10.5-12 mg/dL [2.7-3 mmol/L]) and is often accompanied by mild hypophosphatemia and hypermagnesemia. The PTH level is normal or slightly elevated, indicating that this is a PTH-dependent form of hypercalcemia. The parathyroid glands are normal in size or slightly enlarged. The most notable laboratory feature of the disorder is hypocalciuria. The urinary calcium level is usually less than 50 mg/24 h, and the calcium/creatinine clearance ratio is less than 0.01 and calculated as follows:
Hypocalciuria is an intrinsic renal trait; it persists even in patients who have undergone total parathyroidectomy and become hypocalcemic.
Because FBHH is asymptomatic and benign, the most important role of diagnosis is to distinguish it from primary hyperparathyroidism and avoid an unnecessary parathyroidectomy. If subtotal parathyroidectomy is performed, the serum calcium invariably returns shortly to preoperative levels; these persons resist attempts to lower the serum calcium while functioning parathyroid tissue remains. Unfortunate patients with this condition who have undergone total parathyroidectomy are rendered hypoparathyroid and are dependent on calcium and vitamin D supplementation.
The diagnosis must be considered in patients with asymptomatic mild hypercalcemia who are relatively hypocalciuric. However, an unequivocal diagnosis cannot be made biochemically because the serum and urinary calcium and PTH levels all overlap with typical primary hyperparathyroidism. Family screening or sequencing of the CaSR gene in an affected individual is necessary to make the diagnosis and can be obtained commercially. The penetrance of the phenotype is essentially 100%, and affected family members are hypercalcemic throughout life, so if the proband has the disorder, each first-degree relative who is screened has a 50% chance of being hypercalcemic.
Most cases of FBHH are caused by loss-of-function mutations in the CaSR. Loss of the functional output of one CaSR allele shifts the set point for inhibition of PTH release to the right, producing hypercalcemia. The same receptor is expressed in the kidney, where it regulates renal calcium excretion. A variety of point mutations in different exons of the CaSR produce the phenotype. Acquired hypocalciuric hypercalcemia has been described in association with antibodies that interact with the parathyroid CaSRs and block the ability of high [Ca2+] to suppress PTH.
A child of two parents with FBHH may inherit a mutant allele from each parent, producing neonatal severe hypercalcemia, a life-threatening disorder in which failure to sense extracellular calcium causes severe hyperparathyroidism, requiring total parathyroidectomy soon after birth.
As noted above, primary hyperparathyroidism is a feature of both MEN 1 and MEN 2A (see also Chapter 22). The penetrance of primary hyperparathyroidism in MEN 1 is over 90% by age 40. Patients with the MEN 1 syndrome inherit a loss-of-function germline mutation in the tumor suppressor gene MENIN on chromosome 11q12-13. Menin is a nuclear protein that appears to interact with JunD, a member of the AP1 family of transcription factors. A mutation during mitosis of a parathyroid cell that resulted in loss of function in the remaining allele in that cell would abrogate the cell's growth control mechanism and permit clonal expansion of its progeny ultimately to generate the parathyroid tumor. A similar mechanism appears also to operate in a small fraction of sporadic parathyroid adenomas with 11q12-13 deletions.
The penetrance of primary hyperparathyroidism in MEN 2A is about 30%. As discussed in the above section on MCT, the disorder is caused by activating mutations in the RET gene, a tyrosine kinase growth factor receptor. Evidently, the RET gene product is less important for growth of the parathyroids than for thyroid C cells, because the penetrance of primary hyperparathyroidism is fairly low and because (in MEN 2B) a separate class of activating RET mutations produces MCT and pheochromocytoma and very rarely primary hyperparathyroidism. The treatment for parathyroid hyperplasia in MEN 1 or MEN 2 is subtotal parathyroidectomy. The recurrence rate is higher than in sporadic parathyroid hyperplasia and may approach 50% in MEN 1.
Both in patients and in isolated parathyroid cells, exposure to extracellular lithium shifts the set point for inhibition of PTH secretion to the right. Clinically, this results in hypercalcemia and a detectable or elevated level of PTH. Lithium treatment also produces hypocalciuria and is thus a virtual phenocopy of FBHH. Most patients with therapeutic lithium levels for bipolar affective disorder have a slight increase in the serum calcium level, and up to 10% become mildly hypercalcemic, with PTH levels that are high normal or slightly elevated. Lithium treatment can also unmask underlying primary hyperparathyroidism. It is difficult to diagnose primary hyperparathyroidism in a lithium-treated patient, particularly when temporary cessation of lithium therapy is difficult. However, the likelihood of underlying primary hyperparathyroidism is high when the serum calcium is greater than 11.5 mg/dL, and the decision to undertake surgery must be based on clinical criteria. Unfortunately, surgical cure of hyperparathyroidism rarely ameliorates the underlying psychiatric condition.
Malignancy-associated hypercalcemia is the second most common form of hypercalcemia, with an incidence of 15 cases per 100,000 per year—about one-half the incidence of primary hyperparathyroidism. It is, however, much less prevalent than primary hyperparathyroidism, because most patients have a very limited survival. Nonetheless, malignancy-associated hypercalcemia is the most common cause of hypercalcemia in hospitalized patients. The clinical features and pathogenesis of malignancy-associated hypercalcemia are presented in Chapter 21. The treatment of nonparathyroid hypercalcemia is presented later.
Sarcoidosis and Other Granulomatous Disorders
Hypercalcemia is seen in up to 10% of subjects with sarcoidosis. A higher percentage has hypercalciuria. This is due to inappropriately elevated 1,25(OH)2D levels and abnormal vitamin D metabolism. Lymphoid tissue and pulmonary macrophages from affected individuals contain 25(OH)D 1-hydroxylase activity that is not seen in normal individuals. The 1-hydroxylase enzyme, responsible for the overproduction of 1,25(OH)2D in sarcoidosis, is the same as that in the kidney (CYP27B1). 1-Hydroxylase activity in these cells is not readily inhibited by calcium or 1,25(OH)2D, indicating a lack of feedback inhibition. Macrophages expressing the 1-hydroxylase in these patients do not express a normally functioning 24-hydroxylase so that the catabolism and clearance of 1,25(OH)2D in these cells are lacking. This makes these subjects vulnerable to hypercalcemia or hypercalciuria during periods of increased vitamin D production (eg, summertime with increased sunlight exposure). γ-IFN stimulates 1-hydroxylase activity in these cells, which makes such subjects more vulnerable to altered calcium homeostasis when their disease is active. Glucocorticoids, on the other hand, suppress the inflammation, and subsequently 1-hydroxylase activity, and antagonize 1,25(OH)2D action, providing effective treatment for both the disease and this complication of it.
Other granulomatous diseases are associated with abnormal vitamin D metabolism, resulting in hypercalcemia and/or hypercalciuria. These disorders include tuberculosis, berylliosis, disseminated coccidioidomycosis, histoplasmosis, leprosy, and pulmonary eosinophilic granulomatosis. Furthermore, a substantial number of subjects with Hodgkin or non-Hodgkin lymphomas develop hypercalcemia associated with inappropriately elevated 1,25(OH)2D levels. Although most such patients are normocalcemic on presentation, they may be hypercalciuric, and this should be evaluated as part of the workup. Hypercalcemia and hypercalciuria may not become apparent until situations such as increased sunlight exposure or vitamin D and calcium ingestion are experienced. Thus, one should remain alert to this complication even when the initial evaluation of serum calcium is within normal limits.
Mild hypercalcemia is found in about 10% of patients with thyrotoxicosis. The PTH level is suppressed, and the serum phosphate is in the upper normal range. The serum alkaline phosphatase and biochemical markers of bone turnover may be mildly increased. Significant hypercalcemia may develop in patients with thyrotoxicosis, particularly if it is severe and if patients are temporarily immobilized. Thyroid hormone has direct bone-resorbing properties causing a high turnover state, which often eventually progresses to mild osteoporosis.
Hypercalcemia can be a feature of acute adrenal crisis and responds rapidly to glucocorticoid therapy. Animal studies suggest that hemoconcentration is a critical factor. In experimental adrenal insufficiency, ionized [Ca2+] is normal.
Hypercalcemia in patients with pheochromocytoma is most often a manifestation of the MEN 2A syndrome, but hypercalcemia is found occasionally in uncomplicated pheochromocytoma, where it appears to result from secretion of PTHrP by the tumor. About 40% of tumors secreting VIP (VIPomas) are associated with hypercalcemia. The cause is unknown. It is known, however, that high levels of VIP may activate PTH/PTHrP receptors.
The administration of thiazides and related diuretics such as chlorthalidone, metolazone, and indapamide can produce an increase in the serum calcium that is not fully accounted for by hemoconcentration. Hypercalcemia is mild and usually transient, lasting for days or weeks, but occasionally it persists. Thiazide administration can also exacerbate the effects of underlying primary hyperparathyroidism; in fact, thiazide administration was formerly used as a provocative test for hyperparathyroidism in patients with borderline hypercalcemia. Most patients with persistent hypercalcemia while receiving thiazides prove to have primary hyperparathyroidism.
Hypercalcemia may occur in individuals ingesting large doses of vitamin D either therapeutically or accidentally (eg, irregularities in milk product supplementation with vitamin D have been reported). The initial signs and symptoms of vitamin D intoxication include weakness, lethargy, headaches, nausea, and polyuria and are attributable to hypercalcemia and hypercalciuria. Ectopic calcification may occur, particularly in the kidneys, resulting in nephrolithiasis or nephrocalcinosis; other sites include blood vessels, heart, lungs, and skin. Infants appear to be quite susceptible to vitamin D intoxication and may develop disseminated atherosclerosis, supravalvular aortic stenosis, and renal acidosis.
Hypervitaminosis D is readily diagnosed by the very high serum levels of 25(OH)D, because the conversion of vitamin D to 25(OH)D is not tightly regulated. In contrast, 1,25(OH)2D levels are often normal, but not suppressed. This reflects the expected feedback regulation of 1,25(OH)2D production by the elevated calcium and reduced PTH levels. Levels of free 1,25(OH)2D when measured have been found to be increased. This is in part caused by the high levels of 25(OH)D that displace 1,25(OH)2D from DBP, raising the ratio of free:total 1,25(OH)2D. The elevated free concentration of 1,25(OH)2D, plus the intrinsic biologic effects of the elevated 25(OH)D concentration, combine to increase intestinal calcium absorption and bone resorption. The hypercalciuria, which is invariably seen, may lead to dehydration and coma as a result of hyposthenuria, prerenal azotemia, and worsening hypercalcemia due, in part, to decreased renal clearance.
The dose of vitamin D required to induce toxicity varies among patients, reflecting differences in absorption, storage, and subsequent metabolism of the vitamin as well as in target tissue response to the active metabolites. For example, an elderly patient is likely to have reduced intestinal calcium transport and renal production of 1,25(OH)2D. Such an individual may be able to tolerate 50,000 to 100,000 units of vitamin D daily (although these levels far exceed daily requirements). However, patients with unsuspected hyperparathyroidism receiving such doses for the treatment of osteoporosis are more likely to experience hypercalcemia. Treatment consists of withdrawing the vitamin D, rehydration, reducing calcium intake, and administering glucocorticoids, which antagonize the ability of 1,25(OH)2D to stimulate intestinal calcium absorption. Excess vitamin D is slowly cleared from the body (weeks to months), so treatment is prolonged.
Excessive ingestion of vitamin A, usually from self-medication with vitamin A preparations, causes a number of abnormalities, including gingivitis, cheilitis, erythema, desquamation, and hair loss. Bone resorption is increased, leading to osteoporosis and fractures, hypercalcemia, and hyperostosis. Excess vitamin A causes hepatosplenomegaly with hypertrophy of fat storage cells, fibrosis, and sclerosis of central veins. Many of these effects can be attributed to the effects of vitamin A on cellular membranes. Under normal circumstances, such effects are prevented because vitamin A is bound to retinol-binding protein (RBP), and its release from the liver is regulated. In vitamin A toxicity, however, these protective mechanisms are overcome, and retinol and its retinyl esters appear in blood unbound to RBP. The mechanism by which vitamin A stimulates bone resorption is not clear.
The ingestion of large quantities of calcium together with an absorbable alkali can produce hypercalcemia with alkalosis, renal impairment, and often nephrocalcinosis. The syndrome was more common when absorbable antacids were the standard treatment for peptic ulcer disease, but it is still seen occasionally. This is the only recognized example of pure absorptive hypercalcemia. The details of its pathogenesis are poorly understood.
In immobilized patients there is a marked increase in bone resorption, which often produces hypercalciuria and occasionally hypercalcemia, mainly in individuals with a preexisting high bone turnover state, such as adolescents and patients with thyrotoxicosis or Paget disease. Intact PTH and PTHrP levels are suppressed. The disorder remits with the restoration of activity. If acute treatment is required, bisphosphonates appear to be the treatment of choice.
Hypercalcemia is often seen when renal failure is precipitated by rhabdomyolysis and usually occurs during the early recovery stage, presumably as calcium deposits are mobilized from damaged muscle tissue. It typically resolves over a few weeks.
Both PTH and 1,25(OH)2D maintain a normal serum calcium and are thus central to the defense against hypocalcemia. Hypocalcemic disorders are best understood as failures of the adaptive response. Thus, chronic hypocalcemia can result from a failure to secrete PTH, altered responsiveness to PTH, a deficiency of vitamin D, or a resistance to vitamin D (Table 8–7). Acute hypocalcemia is most often the consequence of an overwhelming challenge to the adaptive response such as rhabdomyolysis, in which a flood of phosphate from injured skeletal muscle inundates the extracellular fluid.
Table 8–7 Causes of Hypocalcemia. ||Download (.pdf)
Table 8–7 Causes of Hypocalcemia.
Deposition of metals (iron, copper, aluminum)
Functional (in hypomagnesemia)
Resistance to PTH action
Medications that block osteoclastic bone resorption
Failure to produce 1,25(OH)2D normally
Vitamin D deficiency
Hereditary vitamin D-dependent rickets, type 1 (renal 25-OH-vitamin D 1alpha-hydroxylase deficiency)
Resistance to 1,25(OH)2D action
Hereditary vitamin D-dependent rickets, type 2 (defective VDR)
Acute complexation or deposition of calcium
Crush injury with myonecrosis
Rapid tumor lysis
Parenteral phosphate administration
Excessive enteral phosphate
Oral (phosphate-containing antacids)
Citrated blood transfusion
Rapid, excessive skeletal mineralization
Hungry bones syndrome
Vitamin D therapy for vitamin D deficiency
Most of the symptoms and signs of hypocalcemia occur because of increased neuromuscular excitability (tetany, paresthesias, seizures, organic brain syndrome) or because of deposition of calcium in soft tissues (cataract, calcification of basal ganglia).
Clinically, the hallmark of severe hypocalcemia is tetany. Tetany is a state of spontaneous tonic muscular contraction. Overt tetany is often heralded by tingling paresthesias in the fingers and around the mouth, but the classic muscular component of tetany is carpopedal spasm. This begins with adduction of the thumb, followed by flexion of the metacarpophalangeal joints, extension of the interphalangeal joints, and flexion of the wrists to produce the main d'accoucheur posture (Figure 8–18). These involuntary muscle contractions are painful. Although the hands are most typically involved, tetany can involve other muscle groups, including life-threatening spasm of laryngeal muscles. Electromyographically, tetany is typified by repetitive motor neuron action potentials, usually grouped as doublets. Tetany is not specific for hypocalcemia. It also occurs with hypomagnesemia and metabolic alkalosis, and the most common cause of tetany is respiratory alkalosis from hyperventilation.
Position of fingers in carpal spasm due to hypocalcemic tetany. (Reproduced, with permission, from Ganong WF. Review of Medical Physiology. 16th ed. Originally published by Appleton & Lange. Copyright 1993 by The McGraw-Hill Companies, Inc.)
Lesser degrees of neuromuscular excitability (eg, serum [Ca] 7.5-8.5 mg/dL) produce latent tetany, which can be elicited by testing for Chvostek and Trousseau signs. Chvostek sign is elicited by tapping the facial nerve about 2 cm anterior to the earlobe, just below the zygoma. The response is a contraction of facial muscles ranging from twitching of the angle of the mouth to hemifacial contractions. The specificity of the test is low; about 25% of normal individuals have a mild Chvostek sign. Trousseau sign is elicited by inflating a blood pressure cuff to about 20 mm Hg above systolic pressure for 3 minutes. A positive response is carpal spasm. Trousseau sign is more specific than Chvostek, but 1% to 4% of normal individuals have positive Trousseau signs.
Hypocalcemia predisposes to focal or generalized seizures. Other central nervous system effects of hypocalcemia include pseudotumor cerebri, papilledema, confusion, lassitude, and organic brain syndrome. Twenty percent of children with chronic hypocalcemia develop mental retardation. The basal ganglia are often calcified in patients with long-standing hypoparathyroidism or PHP. This is usually asymptomatic but can produce a variety of movement disorders.
Other Manifestations of Hypocalcemia
Cardiac effects—Repolarization is delayed, with prolongation of the QT interval. Excitation-contraction coupling may be impaired, and refractory congestive heart failure is sometimes observed, particularly in patients with underlying cardiac disease.
Ophthalmologic effects—Subcapsular cataract is common in chronic hypocalcemia, and its severity is correlated with the duration and level of hypocalcemia.
Dermatologic effects—The skin is often dry and flaky and the nails brittle.
Hypoparathyroidism may be surgical, autoimmune, familial, or idiopathic. The signs and symptoms are those of chronic hypocalcemia. Biochemically, the hallmarks of hypoparathyroidism are hypocalcemia, hyperphosphatemia (because the phosphaturic effect of PTH is lost), and an inappropriately low or undetectable PTH level.
The most common cause of hypoparathyroidism is surgery on the neck, with removal or destruction of the parathyroid glands. The operations most often associated with hypoparathyroidism are cancer surgery, total thyroidectomy, and parathyroidectomy, but the skill and experience of the surgeon are more important predictors than the nature of the operation. Tetany ensues 1 or 2 days postoperatively, but about half of patients with postoperative tetany recover sufficiently so they do not require long-term replacement therapy. In these cases, a devitalized parathyroid remnant has recovered its blood supply and resumes secretion of PTH. In some patients, hypocalcemia may not become evident until years after the procedure. Surgical hypoparathyroidism is the presumptive diagnosis for hypocalcemia in any patient with a surgical scar on the neck.
In patients with severe hyperparathyroid bone disease preoperatively, a syndrome of postoperative hypocalcemia can follow successful parathyroidectomy. This is the hungry bones syndrome, which results from avid uptake of calcium and phosphate by the bones. The parathyroids, although intact, cannot compensate. The syndrome is usually seen in patients with an elevated preoperative serum alkaline phosphatase and/or severe uremic secondary hyperparathyroidism. It can usually be distinguished from surgical hypoparathyroidism by the serum phosphorus, which is low in the hungry bones syndrome, because of skeletal avidity for phosphate, and high in hypoparathyroidism, and by the serum PTH, which becomes appropriately elevated in the hungry bones syndrome.
Acquired hypoparathyroidism is sometimes seen in the setting of polyglandular endocrinopathies. Most commonly, it is associated with primary adrenal insufficiency and mucocutaneous candidiasis in the syndrome of autoimmune polyglandular syndrome type 1 (APS1) (see Chapter 3). The typical age at onset of hypoparathyroidism is 5 to 9 years. A similar form of hypoparathyroidism can occur as an isolated finding. The age at onset of idiopathic hypoparathyroidism is 2 to 10 years, and there is a preponderance of female cases. Circulating parathyroid antibodies are common in both APS1 and in isolated hypoparathyroidism. Many patients have antibodies that recognize the CaSR. Many patients with autoimmune hypoparathyroidism have antibodies reactive with NALP5 (NACHT leucine-rich-repeat protein 5), an intracellular signaling molecule expressed in the parathyroid. The pathogenetic role of any of these antibodies is not yet clarified. APS1 is an autosomal recessive disorder in which mutations are found in the AIRE (autoimmune regulator) protein. AIRE is a transcription factor involved in negative selection in the thymus and periphery.
Another form of autoimmune hypoparathyroidism has been reported in patients with autoantibodies to the CaSR that functionally activate it and suppress PTH secretion. These rare cases have been detected along with other autoimmune disorders such as Addison disease and Hashimoto thyroiditis.
Hypoparathyroidism is an uncommon disorder and presents in familial forms transmitted as either autosomal dominant or recessive traits. Autosomal recessive hypoparathyroidism occurs in families with PTH gene mutations that interfere with the normal processing of PTH. Another autosomal recessive form of this disease is due to a deletion of the 5′ sequence of the gene encoding the transcription factor glial cell missing 2, which is necessary for parathyroid gland development. Hypoparathyroidism is evident in the newborn period because of parathyroid gland agenesis.
Autosomal dominant hypoparathyroidism can be due to point mutations in the CaSR gene, which render the protein constitutively active. This property enables the receptor to mediate suppression of PTH secretion at normal and even subnormal serum calcium levels. Several families with different mutations have been described; affected individuals typically have mild hypoparathyroidism (mildly reduced serum [Ca2+] and PTH levels). These patients also demonstrate marked hypercalciuria due to CaSR mutations in their kidneys. The set point for calcium-induced suppression of PTH secretion in these patients is shifted to the left as is the effect of serum [Ca2+] on renal calcium excretion. Thus, this syndrome is the mirror image of FBHH. Therapy is often not necessary and risks precipitating even greater degrees of hypercalciuria, nephrocalcinosis, and renal stones.
Other Causes of Hypoparathyroidism
Neonatal hypoparathyroidism can be part of the DiGeorge syndrome (dysmorphic facies, cardiac defects, immune deficiency, and hypoparathyroidism) due to a microdeletion (or other genetic abnormalities) on chromosome 22q11.2; the HDR syndrome (hypoparathyroidism, sensorineural deafness, and renal anomalies) due to mutations in or deletion of an allele of the GATA3 transcription factor; and other rare conditions. Transfusion-dependent individuals with thalassemia or red cell aplasia who survive into the third decade of life are susceptible to hypoparathyroidism as the result of iron deposition in the parathyroid glands. Copper deposition can cause hypoparathyroidism in Wilson disease. Infiltration with metastatic carcinoma is a very rare cause of hypoparathyroidism.
Severe magnesium depletion temporarily paralyzes the parathyroid glands, preventing secretion of PTH. Magnesium depletion also blunts the actions of PTH on target organs (kidney and bone) to counteract the hypocalcemia. This is seen with magnesium losses due to gastrointestinal and renal disorders and alcoholism. The syndrome responds immediately to infusion of magnesium. As discussed above in the section on regulation of PTH secretion, magnesium is probably required for effective stimulus-secretion coupling in the parathyroids.
PHP is a genetic disorder of target-organ unresponsiveness to PTH. Biochemically, it mimics hormone-deficient forms of hypoparathyroidism, with hypocalcemia and hyperphosphatemia, but the PTH level is elevated, and there is a markedly blunted response to the administration of PTH (see Diagnosis, later).
Two distinct forms of PHP are recognized. PHP type IB is a disorder of isolated resistance to PTH, which presents with the biochemical features of hypocalcemia, hyperphosphatemia, and secondary hyperparathyroidism. PHP type IA has, in addition to these biochemical features, a characteristic somatic phenotype known as Albright hereditary osteodystrophy (AHO). This consists of short stature, round face, short neck, obesity, brachydactyly (short digits), shortened metatarsals, subcutaneous ossifications, and often reduced intelligence. Because of shortening of the metacarpal bones—most often the fourth and fifth metacarpals—affected digits have a dimple, instead of a knuckle, when a fist is made (Figure 8–19). Primary hypothyroidism is frequently seen. Less commonly, these patients have abnormalities of reproductive function—oligomenorrhea in females and infertility in males due to primary hypogonadism. Interestingly, certain individuals in families with PHP inherit the somatic phenotype of AHO without any disorder of calcium metabolism; this state, which mimics PHP, is called pseudo-PHP or PPHP.
Hands of a patient with pseudohypoparathyroidism. A: Note the short fourth fingers. B: Note the “absent“ fourth knuckle. C: Film shows the short fourth metacarpal. (Reproduced, with permission, from Potts JT. Pseudohypoparathyroidism: clinical features; signs and symptoms; diagnosis and differential diagnosis. In: Stanbury JB, Wyngaarden JB, Fredrickson DS, eds. The Metabolic Basis of Inherited Disease. 4th ed. McGraw-Hill; 1978.)
PHP type IA is caused by the loss of function of one allele (haploinsufficiency) of the gene encoding the stimulatory G protein alpha subunit, (Gs alpha or GNAS). This abnormality is predicted to produce only 50% of the normal levels of the alpha subunit of the heterotrimeric Gs, which couples the PTH receptor to adenylyl cyclase. Patients with PHP type IA have a markedly blunted response of urinary cAMP to administration of PTH. Because Gs also couples many other receptors to adenylyl cyclase, the expected result of this mutation would be a generalized disorder of hormonal unresponsiveness. The presence of primary hypothyroidism and primary hypogonadism in these patients indicates that resistance to TSH, LH, and FSH occurs fairly commonly. Responsiveness to other hormones (eg, ACTH, glucagon) is fairly normal. Thus, a 50% loss of the Gs alpha protein produces resistance to some hormones but not others. Gs alpha is also deficient in individuals with PPHP, who have AHO but normal responsiveness to PTH. Thus, a mutation in the Gs alpha gene invariably produces AHO but only sometimes produces resistance to PTH, suggesting that the occurrence of a metabolic phenotype is determined by other factors described below (Table 8–8).
Table 8–8 Features of Pseudohypoparathyroidism. ||Download (.pdf)
Table 8–8 Features of Pseudohypoparathyroidism.
|PHP 1A||PPHPa||PHP 1B|
|Response to PTH||No||Yes||No|
|Albright hereditary osteodystrophy||Yes||Yes||No|
|GNAS coding region mutation||Yes||Yes||No|
|GNAS regulatory region mutation or deletion||No||No||Yes|
|Generalized target organ unresponsiveness||Yes||No||No|
In PHP type IB, there is resistance to PTH but no somatic phenotype (ie, AHO), and levels of Gs alpha protein in red blood cell or fibroblast membranes are normal. The disorder, however, is also linked to the GNAS locus, but it does not involve mutations in the coding region of GNAS. Instead epigenetic defects in GNAS are present that cause the differentially methylated region at exon A/B to lose its imprinting. Most cases demonstrate a maternally derived 3-kb deletion of DNA sequences located more than 200 kb centromeric of the GNAS locus at the STX16 locus. Other deletions remove this entire differentially methylated region—a key regulator of the levels of GNAS transcription. Transcription directed by this (unmethylated) promoter does not produce appropriate levels of Gs alpha protein in the renal cortex where this biallelic promoter activity is important. Thus, abnormal methylation of GNAS regulatory sequences plays a key role in the pathogenesis of PHP1B.
PHP type IA is inherited as an autosomal dominant trait. Individuals who have acquired the trait from their fathers almost always present with PPHP and lack hormone resistance. When the mutant allele is derived from the mother, PHP with hormone resistance is always present. This pattern of inheritance is due to genomic imprinting of the GNAS1 locus. In the kidney cortex, the maternal allele is preferentially expressed and the paternal allele is silenced. Thus, if the mutant GNAS1 allele is maternally derived, the resulting offspring will have PHP; if the mutant GNAS1 allele is paternally derived (and therefore silenced), the resulting offspring will have PPHP. Tissue-specific imprinting of the GNAS1 gene, therefore, determines the expression of hormone resistance in the kidney and thyroid. The expression of AHO does not depend on imprinting mechanisms and occurs in PHP type IA and PPHP.
Several disorders present with hypocalcemia and secondary hyperparathyroidism (eg, vitamin D deficiency), but when these features occur together with hyperphosphatemia or AHO, this suggests the diagnosis of PHP. To confirm that resistance to PTH is present, the patient can be challenged with PTH (the Ellsworth-Howard test). For this purpose, synthetic human PTH(1-34) (teriparatide acetate, 3 IU/kg body weight) is infused intravenously over 10 minutes during a water diuresis, and urine is collected during the hour preceding the infusion, during the half-hour following the infusion, 30 to 60 minutes after the infusion, and 1 to 2 hours after the infusion and assayed for cAMP and creatinine. Data are expressed as nanomoles of cAMP per liter of glomerular filtrate, based on creatinine measurements. Normally, there is an increase in urinary cAMP of more than 300 nmol/L glomerular filtrate after administration of PTH. The use of the urinary phosphate response as a gauge of PTH responsiveness is much less reliable. For practical purposes, hypocalcemia, hyperphosphatemia, elevated PTH levels, and normal levels of vitamin D metabolites (with or without AHO) confirm the presence of resistance to PTH.
Vitamin D deficiency results from one or more factors: inadequate sunlight exposure, inadequate nutrition, or malabsorption. In addition, drugs that activate the catabolism of vitamin D and its metabolites, such as phenytoin and phenobarbital, can precipitate vitamin D deficiency in subjects with marginal vitamin D status. Although the human skin is capable of producing sufficient amounts of vitamin D if exposed to sunlight of adequate intensity, institutionalized patients frequently do not get adequate exposure. Furthermore, the fear of skin cancer has led many to avoid sunlight exposure or to apply protective agents that block the ultraviolet portion of sunlight from reaching the lower reaches of the epidermis where most of the vitamin D is produced. Heavily pigmented and elderly individuals have less efficient production of vitamin D for a given exposure to ultraviolet irradiation. Serum levels of 25(OH)D are used to indicate vitamin D status. Although there is no consensus on what level of 25(OH)D constitutes sufficiency, 30 ng/mL has become the preferred target in North America. With that standard, a large portion of the population is vitamin D insufficient. A recent NHANES survey found that in the population over age 60, 67% of Caucasians, 82% of Hispanics, and 88% of African Americans had 25(OH)D levels below 30 ng/mL. Studies of hospitalized patients or those in nursing homes show almost universal vitamin D insufficiency if not frank deficiency. The intensity of sunlight is an important factor that limits effective vitamin D production as a function of season (summer > winter) and latitude (less intense the higher the latitude). The supplementation of milk has reduced the incidence of vitamin D deficiency in the United States, but most countries do not follow this practice. Even in the United States, severe vitamin D deficiency and rickets may occur in children of vegetarian mothers who avoid milk products (and presumably have reduced vitamin D stores) and in children who are not weaned to vitamin D-supplemented milk by age 2. Breast milk contains little vitamin D, although vitamin D content can be increased by supplementing the mother. Adults who avoid milk as well as sunlight are likewise at risk. Individuals with a variety of small bowel, pancreatic, and biliary tract disease and those after partial gastrectomy or intestinal bypass surgery have reduced capacity to absorb the vitamin D from the diet.
The clinical features of individuals with severe vitamin D deficiency will be discussed more thoroughly in the section on “Osteomalacia and Rickets.” Severe vitamin D deficiency should be suspected in individuals complaining of lethargy, proximal muscle weakness, and bone pain who have frankly low or low normal serum calcium and phosphate and low urine calcium on routine biochemical evaluation. A low serum 25(OH)D level is diagnostic in this setting. 1,25(OH)2D levels are often normal and reflect the increased 1-hydroxylase activity in these subjects that is responding appropriately to the increased PTH levels as well as the low serum calcium and phosphate levels. However, there is increasing awareness that less severe degrees of vitamin D deficiency may not present with obvious musculoskeletal signs and symptoms. These individuals may be more susceptible to conditions such as hyperparathyroidism, osteoporosis, increased risk of falls and fractures, but also increased infections, hypertension, increased cardiovascular disease, diabetes mellitus, and various malignancies. Solid data from large-scale randomized placebo controlled clinical trials demonstrating cause and effect for vitamin D deficiency and many of these disorders are lacking, although animal studies and a large body of epidemiologic evidence and case control studies point in this direction.
The goal in treating severe vitamin D deficiency manifesting as rickets or osteomalacia is to normalize the clinical, biochemical, and radiologic abnormalities without producing hypercalcemia, hyperphosphatemia, hypercalciuria, nephrolithiasis, or ectopic calcification. To realize this goal, patients must be followed carefully. As the bone lesions heal or the underlying disease improves, the dosage of vitamin D, calcium, or phosphate needs to be adjusted to avoid such complications. With the appreciation that most individuals have a less severe form of vitamin D deficiency and do not have obvious signs or symptoms associated with rickets or osteomalacia, the goal of treatment is to achieve a level of 25(OH)D that existing data indicate will reduce the predisposition of such individuals to the numerous diseases associated with vitamin D deficiency. Correction of vitamin D deficiency can usually be achieved by the weekly administration of 50,000 IU ergocalciferol for 6 to 8 weeks followed by replacement doses of 800 to 2000 IU/d based on maintenance of adequate serum 25(OH)D levels. Patients with malabsorption may respond to larger amounts of vitamin D (25,000-100,000 IU/d or one to three times per week). 25(OH)D (50-100 μg/d) is better absorbed than vitamin D and may be used if malabsorption of vitamin D is a limiting factor, but is not readily available in the United States. Calcitriol (1,25(OH)2D) and its analogs are not appropriate therapy for patients with vitamin D deficiency because of the likely requirement for vitamin D metabolites other than 1,25(OH)2D and the advantage of providing adequate substrate (25(OH)D) for tissues capable of producing their own 1,25(OH)2D as the need arises (eg, as in the immune response). The exception to this rule is in patients with renal failure incapable of producing adequate 1,25(OH)2D. Vitamin D therapy should be supplemented with 1 to 3 g of elemental calcium per day. Care must be taken in managing patients with vitamin D deficiency who also have elevated PTH levels, because long-standing vitamin D deficiency may produce a degree of autonomy in the parathyroid glands such that rapid replacement with calcium and vitamin D could result in hypercalcemia or hypercalciuria. A listing of available vitamin D metabolites and analogs with their main indications for clinical use is presented in Table 8–2.
Pseudovitamin D Deficiency
Pseudovitamin D deficiency is a rare autosomal recessive disease in which rickets is accompanied by low levels of 1,25(OH)2D but normal levels of 25(OH)D. The disease is due to mutations in the 25(OH)D 1-hydroxylase gene (CYP27B1) that render it nonfunctional. Both alleles need to be defective in order for the disease to be manifest. Although affected patients do not respond to doses of vitamin D that are effective in subjects with vitamin D deficiency, they can respond to pharmacologic doses of vitamin D and to physiologic doses of calcitriol, which is the preferred treatment.
Hereditary Vitamin D–Resistant Rickets
Hereditary vitamin D–resistant rickets is a rare autosomal recessive disease that presents in childhood with rickets similar to that seen in patients with vitamin D deficiency. Many of these patients also have alopecia, which is not characteristic of vitamin D deficiency or pseudovitamin D deficiency. The biochemical changes are similar to those reported in subjects with vitamin D deficiency except that the 1,25(OH)2D levels are generally very high. The disease is caused by inactivating mutations in the VDR gene. The location of the mutation can affect the severity of the disease. In particular, mutations in the DNA-binding domain (exons 2, 3) that prevent DNA binding and mutations in the ligand-binding domain (exons 5-7) that prevent 1,25(OH)2D binding lead to a more. The latter mutations may alter but not inhibit DNA/ligand binding. These patients are treated with large doses of calcitriol and dietary calcium and may show partial or complete remission as they grow older. An animal model of this disease (inactivation or knockout of both VDR alleles) demonstrates that the bone disease can be corrected with high dietary intake of calcium and phosphate, although the alopecia is not altered. This disease points to a role for the VDR in epidermis and hair development that is independent of its activity in the intestine and bone.
Other Hypocalcemic Disorders
Hypoalbuminemia produces a low total serum [Ca2+] because of a reduction in the bound fraction of calcium, but the ionized [Ca2+] is normal. The ionized [Ca2+] can be determined directly, or the effect of hypoalbuminemia can be roughly corrected for by using the following formula:
Corrected serum calcium = Measured serum calcium + (0.8) (4 − Measured serum albumin)
Thus, in a patient with a serum [Ca2+] of 7.8 mg/dL and a serum albumin of 2 g/dL, the corrected serum [Ca2+] is 7.8 + (0.8)(4 − 2) = 9.4 mg/dL.
Several disorders produce acute hypocalcemia even if homeostatic mechanisms are intact, simply because they overwhelm these mechanisms. Acute hyperphosphatemia resulting from rhabdomyolysis or tumor lysis, often in the setting of renal insufficiency, may produce severe symptomatic hypocalcemia. Transfusion of large volumes of cit-rated blood causes acute hypocalcemia by complexation of calcium as calcium citrate. In this instance, total calcium may be normal, but the ionized fraction is reduced. In acute pancreatitis, hypocalcemia is an ominous prognostic sign. The mechanism of hypocalcemia is sequestration of calcium by saponification with fatty acids, which are produced in the retroperitoneum by the action of pancreatic lipases. Skeletal mineralization, when very rapid, can cause hypocalcemia. This is seen in the hungry bones syndrome, which was discussed above in the section on surgical hypoparathyroidism, and occasionally with widespread osteoblastic metastases from prostatic carcinoma.