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InternalMed_Harrison. PRIMARY HYPERPARATHYROIDISM Natural History and Incidence Primary hyperparathyroidism is a generalized disorder of calcium, phosphate, and bone metabolism due to an increased secretion of PTH. The elevation of circulating hormone usually leads to hypercalcemia and hypophosphatemia. There is great variation in the manifestations. Patients may present with multiple signs and symptoms, including recurrent nephrolithiasis, peptic ulcers, mental changes, and, less frequently, extensive bone resorption. However, with greater awareness of the disease and wider use of multiphasic screening tests, including measurements of blood calcium, the diagnosis is frequently made in patients who have no symptoms and minimal, if any, signs of the disease other than hypercalcemia and elevated levels of PTH. The manifestations may be subtle, and the disease may have a benign course for many years or a lifetime. This milder form of the disease is usually termed asymptomatic hyperparathyroidism. Rarely,


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InternalMed_Harrison. The manifestations may be subtle, and the disease may have a benign course for many years or a lifetime. This milder form of the disease is usually termed asymptomatic hyperparathyroidism. Rarely, hyperparathyroidism develops or worsens abruptly and causes severe complications such as marked dehydration and coma, so-called hypercalcemic parathyroid crisis.


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InternalMed_Harrison. The annual incidence of the disease is calculated to be as high as 0.2% in patients >60, with an estimated prevalence, including undiscovered asymptomatic patients, of ≥1%; some reports suggest the incidence may be declining. If confirmed, these changing estimates may reflect less frequent routine testing of serum calcium in recent years, earlier overestimates in incidence, or unknown factors. The disease has a peak incidence between the third and fifth decades but occurs in young children and in the elderly. Etiology Parathyroid tumors are most often encountered as isolated adenomas without other endocrinopathy. They may also arise in hereditary syndromes such as MEN syndromes. Parathyroid tumors may also arise as secondary to underlying disease (excessive stimulation in secondary hyperparathyroidism, especially chronic renal failure) or after other forms of excessive stimulation such as lithium therapy. These etiologies are discussed below.


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InternalMed_Harrison. Solitary adenomaS A single abnormal gland is the cause in ~80% of patients; the abnormality in the gland is usually a benign neoplasm or adenoma and rarely a parathyroid carcinoma. Some surgeons and pathologists report that the enlargement of multiple glands is common; double adenomas are reported. In ~15% of patients, all glands are hyperfunctioning; chief cell parathyroid hyperplasia is usually hereditary and frequently associated with other endocrine abnormalities.


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InternalMed_Harrison. Hereditary SyndromeS and multiple paratHyroid tumorS Hereditary hyperparathyroidism can occur without other endocrine abnormalities but is usually part of a multiple endocrine neoplasia (MEN) syndrome (Chap. 408). MEN 1 (Wermer’s syndrome) consists of hyperparathyroidism and tumors of the pituitary and pancreas, often associated with gastric hypersecretion and peptic ulcer disease (Zollinger-Ellison syndrome). MEN 2A is characterized by pheochromocytoma and medullary carcinoma of the thyroid, as well as hyperparathyroidism; MEN 2B has additional associated features such as multiple neuromas but usually lacks hyperparathyroidism. Each of these MEN syndromes is transmitted in an apparent autosomal dominant manner, although, as noted below, the genetic basis of MEN 1 involves biallelic loss of a tumor suppressor.


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InternalMed_Harrison. The hyperparathyroidism jaw tumor (HPT-JT) syndrome occurs in families with parathyroid tumors (sometimes carcinomas) in association with benign jaw tumors. This disorder is caused by mutations in CDC73 (HRPT2), and mutations in this gene are also observed in parathyroid cancers. Some kindreds exhibit hereditary hyperparathyroidism without other endocrinopathies. This disorder is often termed nonsyndromic familial isolated hyperparathyroidism (FIHP). There is speculation that these families may be examples of variable expression of the other syndromes such as MEN 1, MEN 2, or the HPT-JT syndrome, but they may also have distinctive, still unidentified genetic causes.


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InternalMed_Harrison. Pathology Adenomas are most often located in the inferior parathyroid glands, but in 6–10% of patients, parathyroid adenomas may be located in the thymus, the thyroid, the pericardium, or behind the esophagus. Adenomas are usually 0.5–5 g in size but may be as large as 10–20 g (normal glands weigh 25 mg on average). Chief cells are predominant in both hyperplasia and adenoma. With chief cell hyperplasia, the enlargement may be so asymmetric that some involved glands appear grossly normal. If generalized hyperplasia is present, however, histologic examination reveals a uniform pattern of chief cells and disappearance of fat even in the absence of an increase in gland weight. Thus, microscopic examination of biopsy specimens of several glands is essential to interpret findings at surgery.


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InternalMed_Harrison. Parathyroid carcinoma is often not aggressive. Long-term survival without recurrence is common if at initial surgery the entire gland is removed without rupture of the capsule. Recurrent parathyroid carcinoma is usually slow-growing with local spread in the neck, and surgical correction of recurrent disease may be feasible. Occasionally, however, parathyroid carcinoma is more aggressive, with distant metastases (lung, liver, and bone) found at the time of initial operation. It may be difficult to appreciate initially that a primary tumor is carcinoma; increased numbers of mitotic figures and increased fibrosis of the gland stroma may precede invasion. The diagnosis of carcinoma is often made in retrospect. Hyperparathyroidism from a parathyroid carcinoma may be indistinguishable from other forms of primary hyperparathyroidism but is usually more severe clinically. A potential clue to the diagnosis is offered by the degree of calcium elevation. Calcium values of 3.5–3.7 mmol/L (14–15


InternalMed_Harrison

InternalMed_Harrison. forms of primary hyperparathyroidism but is usually more severe clinically. A potential clue to the diagnosis is offered by the degree of calcium elevation. Calcium values of 3.5–3.7 mmol/L (14–15 mg/dL) are frequent with carcinoma and may alert the surgeon to remove the abnormal gland with care to avoid capsular rupture. Recent findings concerning the genetic basis of parathyroid carcinoma (distinct from that of benign adenomas) indicate the need, in these kindreds, for family screening (see below).


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InternalMed_Harrison. As in many other types of neoplasia, two fundamental types of genetic defects have been identified in parathyroid gland tumors: (1) overactivity of protooncogenes and (2) loss of function of tumor-suppressor genes. The former, by definition, can lead to uncontrolled cellular growth and function by activation (gain-of-function mutation) of a single allele of the responsible gene, whereas the latter requires loss of function of both allelic copies. Biallelic loss of function of a tumor-suppressor gene is usually characterized by a germline defect (all cells) and an additional somatic deletion/mutation in the tumor (Fig. 424-3).


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InternalMed_Harrison. Mutations in the MEN1 gene locus, encoding the protein MENIN, 2471 on chromosome 11q13 are responsible for causing MEN 1; the normal allele of this gene fits the definition of a tumor-suppressor gene. Inheritance of one mutated allele in this hereditary syndrome, followed by loss of the other allele via somatic cell mutation, leads to monoclonal expansion and tumor development. Also, in ~15–20% of sporadic parathyroid adenomas, both alleles of the MEN1 locus on chromosome 11 are somatically deleted, implying that the same defect responsible for MEN 1 can also cause the sporadic disease (Fig. 424-3A). Consistent with the Knudson hypothesis for two-step neoplasia in certain inherited cancer syndromes (Chap. 101e), the earlier onset of hyperparathyroidism in the hereditary syndromes reflects the need for only one mutational event to trigger the monoclonal outgrowth. In sporadic adenomas, typically occurring later in life, two different somatic events must occur before the MEN1 gene is


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InternalMed_Harrison. the need for only one mutational event to trigger the monoclonal outgrowth. In sporadic adenomas, typically occurring later in life, two different somatic events must occur before the MEN1 gene is silenced.


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InternalMed_Harrison. Other presumptive anti-oncogenes involved in hyperparathyroidism include a still unidentified gene mapped to chromosome 1p seen in 40% of sporadic parathyroid adenomas and a gene mapped to chromosome Xp11 in patients with secondary hyperparathyroidism and renal failure, who progressed to “tertiary” hyperparathyroidism, now known to reflect monoclonal outgrowths within previously hyperplastic glands. A more complex pattern, still incompletely resolved, arises with genetic defects and carcinoma of the parathyroids. This appears to be due to biallelic loss of a functioning copy of a gene, HRPT2 (or CDC73), originally identified as the cause of the HPT-JT syndrome. Several inactivating mutations have been identified in HRPT2 (located on chromosome 1q21-31), which encodes a 531-amino-acid protein called parafibromin. The responsible genetic mutations in HRPT2 appear to be necessary, but not sufficient, for parathyroid cancer.


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InternalMed_Harrison. In general, the detection of additional genetic defects in these parathyroid tumor–related syndromes and the variations seen in Somatic mutation of one copy of the Clonal progenitor cell lacks HRPT2 tumor suppressor gene on functional HRPT2 gene product 1q21–31 no adverse consequences A to parathyroid cell


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InternalMed_Harrison. FIGURE 424-3 A. Schematic diagram indicating molecular events in tumor susceptibility. The patient with the hereditary abnormality (multiple endocrine neoplasia [MEN]) is envisioned as having one defective gene inherited from the affected parent on chromosome 11, but one copy of the normal gene is present from the other parent. In the monoclonal tumor (benign tumor), a somatic event, here partial chromosomal deletion, removes the remaining normal gene from a cell. In nonhereditary tumors, two successive somatic mutations must occur, a process that takes a longer time. By either pathway, the cell, deprived of growth-regulating influence from this gene, has unregulated growth and becomes a tumor. A different genetic locus also involving loss of a tumor-suppressor gene termed HRPT2 is involved in the pathogenesis of parathyroid carcinoma. (From A Arnold: J Clin Endocrine Metab 77:1108, 1993. Copyright 1993, The Endocrine Society.) B. Schematic illustration of the mechanism and


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InternalMed_Harrison. is involved in the pathogenesis of parathyroid carcinoma. (From A Arnold: J Clin Endocrine Metab 77:1108, 1993. Copyright 1993, The Endocrine Society.) B. Schematic illustration of the mechanism and consequences of gene rearrangement and overexpression of the PRAD1 protooncogene (pericentromeric inversion of chromosome 11) in parathyroid adenomas. The excessive expression of PRAD1 (a cell cycle control protein, cyclin D1) by the highly active parathyroid hormone (PTH) gene promoter in the parathyroid cell contributes to excess cellular proliferation. (From J Habener et al, in L DeGroot, JL Jameson [eds]: Endocrinology, 4th ed. Philadelphia, Saunders, 2001; with permission.)


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InternalMed_Harrison. Disorders of the Parathyroid Gland and Calcium Homeostasis Mutant copy of putative tumor Clonal progenitor cell lacks suppressor gene on 11q13 is functional gene product inherited in MEN-1 and present in all parathyroid cells


InternalMed_Harrison

InternalMed_Harrison. Mutation of one allele of same gene may occur somatically in other patients, present in specific parathyroid cell(s) 2472 phenotypic expression/penetrance indicate the multiplicity of the genetic factors responsible. Nonetheless, the ability to detect the presence of the major genetic contributors has greatly aided a more informed management of family members of patients identified in the hereditary syndromes such as MEN 1, MEN 2, and HPT-JT. An important contribution from studies on the genetic origin of parathyroid carcinoma has been the realization that the mutations involve a different pathway than that involved with the benign gland enlargements. Unlike the pathogenesis of genetic alterations seen in colon cancer, where lesions evolve from benign adenomas to malignant disease by progressive genetic changes, the alterations commonly seen in most parathyroid cancers (HRPT2 mutations) are infrequently seen in sporadic parathyroid adenomas. Abnormalities at the Rb gene were the first


InternalMed_Harrison

InternalMed_Harrison. genetic changes, the alterations commonly seen in most parathyroid cancers (HRPT2 mutations) are infrequently seen in sporadic parathyroid adenomas. Abnormalities at the Rb gene were the first to be noted in parathyroid cancer. The Rb gene, a tumor-suppressor gene located on chromosome 13q14, was initially associated with retinoblastoma but has since been implicated in other neoplasias, including parathyroid carcinoma. Early studies implicated allelic deletions of the Rb gene in many parathyroid carcinomas and decreased or absent expression of the Rb protein. However, because there are often large deletions in chromosome 13 that include many genes in addition to the Rb locus (with similar findings in some pituitary carcinomas), it remains possible that other tumor-suppressor genes on chromosome 13 may be playing a role in parathyroid carcinoma. Study of the parathyroid cancers found in some patients with the HPT-JT syndrome has led to identification of a much larger role for mutations


InternalMed_Harrison

InternalMed_Harrison. 13 may be playing a role in parathyroid carcinoma. Study of the parathyroid cancers found in some patients with the HPT-JT syndrome has led to identification of a much larger role for mutations in the HRPT2 gene in most parathyroid carcinomas, including those that arise sporadically, without apparent association with the HPT-JT syndrome. Mutations in the coding region have been identified in 75–80% of all parathyroid cancers analyzed, leading to the conclusion that, with addition of presumed mutations in the noncoding regions, this genetic defect may be seen in essentially all parathyroid carcinomas. Of special importance was the discovery that, in some sporadic parathyroid cancers, germline mutations have been found; this, in turn, has led to careful investigation of the families of these patients and a new clinical indication for genetic testing in this setting. Hypercalcemia occurring in family members (who are also found to have the germline mutations) can lead to the finding, at


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InternalMed_Harrison. patients and a new clinical indication for genetic testing in this setting. Hypercalcemia occurring in family members (who are also found to have the germline mutations) can lead to the finding, at parathyroid surgery, of premalignant parathyroid tumors. Overall, it seems there are multiple factors in parathyroid cancer, in addition to the HRPT2 and Rb gene, although the HRPT2 gene mutation is the most invariant abnormality. RET encodes a tyrosine kinase type receptor; specific inherited germline mutations lead to a constitutive activation of the receptor, thereby explaining the autosomal dominant mode of transmission and the relatively early onset of neoplasia. In the MEN 2 syndrome, the RET protooncogene may be responsible for the earliest disorder detected, the polyclonal disorder (C cell hyperplasia, which then is transformed into a clonal outgrowth—a medullary carcinoma with the participation of other, still uncharacterized genetic defects). In some parathyroid adenomas,


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InternalMed_Harrison. (C cell hyperplasia, which then is transformed into a clonal outgrowth—a medullary carcinoma with the participation of other, still uncharacterized genetic defects). In some parathyroid adenomas, activation of a protooncogene has been identified (Fig. 424-3B). A reciprocal translocation involving chromosome 11 has been identified that juxtaposes the PTH gene promoter upstream of a gene product termed PRAD-1, encoding a cyclin D protein that plays a key role in normal cell division. This translocation plus other mechanisms that cause an equivalent overexpression of cyclin D1 are found in 20–40% of parathyroid adenomas. Mouse models have confirmed the role of several of the major identified genetic defects in parathyroid disease and the MEN syndromes. Loss of the MEN1 gene locus or overexpression of the PRAD-1 protooncogene or the mutated RET protooncogene have been analyzed by genetic manipulation in mice, with the expected onset of parathyroid tumors or medullary carcinoma,


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InternalMed_Harrison. overexpression of the PRAD-1 protooncogene or the mutated RET protooncogene have been analyzed by genetic manipulation in mice, with the expected onset of parathyroid tumors or medullary carcinoma, respectively.


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InternalMed_Harrison. Signs and Symptoms Many patients with hyperparathyroidism are asymptomatic. Manifestations of hyperparathyroidism involve primarily the kidneys and the skeletal system. Kidney involvement, due either to deposition of calcium in the renal parenchyma or to recurrent nephrolithiasis, was present in 60–70% of patients prior to 1970. With earlier detection, renal complications occur in <20% of patients in many large series. Renal stones are usually composed of either calcium oxalate or calcium phosphate. In occasional patients, repeated episodes of nephrolithiasis or the formation of large calculi may lead to urinary tract obstruction, infection, and loss of renal function. Nephrocalcinosis may also cause decreased renal function and phosphate retention.


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InternalMed_Harrison. The distinctive bone manifestation of hyperparathyroidism is osteitis fibrosa cystica, which occurred in 10–25% of patients in series reported 50 years ago. Histologically, the pathognomonic features are an increase in the giant multinucleated osteoclasts in scalloped areas on the surface of the bone (Howship’s lacunae) and a replacement of the normal cellular and marrow elements by fibrous tissue. X-ray changes include resorption of the phalangeal tufts and replacement of the usually sharp cortical outline of the bone in the digits by an irregular outline (subperiosteal resorption). In recent years, osteitis fibrosa cystica is very rare in primary hyperparathyroidism, probably due to the earlier detection of the disease.


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InternalMed_Harrison. Dual-energy x-ray absorptiometry (DEXA) of the spine provides reproducible quantitative estimates (within a few percent) of spinal bone density. Similarly, bone density in the extremities can be quantified by densitometry of the hip or of the distal radius at a site chosen to be primarily cortical. Computed tomography (CT) is a very sensitive technique for estimating spinal bone density, but reproducibility of standard CT is no better than 5%. Newer CT techniques (spiral, “extreme” CT) are more reproducible but are currently available in a limited number of medical centers. Cortical bone density is reduced while cancellous bone density, especially in the spine, is relatively preserved. In symptomatic patients, dysfunctions of the CNS, peripheral nerve and muscle, gastrointestinal tract, and joints also occur. It has been reported that severe neuropsychiatric manifestations may be reversed by parathyroidectomy. When present in symptomatic patients, neuromuscular manifestations may


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InternalMed_Harrison. and joints also occur. It has been reported that severe neuropsychiatric manifestations may be reversed by parathyroidectomy. When present in symptomatic patients, neuromuscular manifestations may include proximal muscle weakness, easy fatigability, and atrophy of muscles and may be so striking as to suggest a primary neuromuscular disorder. The distinguishing feature is the complete regression of neuromuscular disease after surgical correction of the hyperparathyroidism.


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InternalMed_Harrison. Gastrointestinal manifestations are sometimes subtle and include vague abdominal complaints and disorders of the stomach and pancreas. Again, cause and effect are unclear. In MEN 1 patients with hyperparathyroidism, duodenal ulcer may be the result of associated pancreatic tumors that secrete excessive quantities of gastrin (Zollinger-Ellison syndrome). Pancreatitis has been reported in association with hyperparathyroidism, but the incidence and the mechanism are not established. Much attention has been paid in recent years to the manifestations of and optimum management strategies for asymptomatic hyperparathyroidism. This is now the most prevalent form of the disease. Asymptomatic primary hyperparathyroidism is defined as biochemically confirmed hyperparathyroidism (elevated or inappropriately normal PTH levels despite hypercalcemia) with the absence of signs and symptoms typically associated with more severe hyperparathyroidism such as features of renal or bone disease.


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InternalMed_Harrison. Three conferences on the topic have been held in the United States over the past two decades, with the most recent in 2008. The published proceedings include discussion of more subtle manifestations of disease, its natural history (without parathyroidectomy), and guidelines both for indications for surgery and medical monitoring in nonoperated patients.


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InternalMed_Harrison. Issues of concern include the potential for cardiovascular deterioration, the presence of subtle neuropsychiatric symptoms, and the longer-term status of skeletal integrity in patients not treated surgically. The current consensus is that medical monitoring rather than surgical correction of hyperparathyroidism may be justified in certain patients. The current recommendation is that patients who show mild disease, as defined by specific criteria (Table 424-2), can be safely followed under management guidelines (Table 424-3). There is, however, growing uncertainty about subtle disease manifestations and whether surgery is therefore indicated in most patients. Among the issues is the evidence of eventual (>8 years) deterioration in bone mineral density after a decade circulating biologically inactive fragments, detected by the original 2473 first-generation assays. Double-antibody assays are now referred to as second-generation. Such PTH assays have in some centers and testing covered


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InternalMed_Harrison. inactive fragments, detected by the original 2473 first-generation assays. Double-antibody assays are now referred to as second-generation. Such PTH assays have in some centers and testing covered that large PTH fragments, devoid of only the extreme amino- terminal portion of the PTH molecule, are also present in blood and are detected, incorrectly, as intact PTH. These amino-terminally trun-


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InternalMed_Harrison. Bone density T score <−2.5 at any of 3 sitesc aJP Bilezikian et al: Guidelines for the management of asymptomatic primary hyperparathyroidism: Summary statement from the third international workshop. J Clin Endocrinol Metab 94:335, 2009. bCreatinine clearance calculated by Cockcroft-Gault equation or Modification of Diet in Renal Disease (MDRD) equation. cSpine, distal radius, hip. of relative stability. There is concern that this late-onset deterioration in bone density in nonoperated patients could contribute significantly to the well-known age-dependent fracture risk (osteoporosis). One study reported significant and sustained improvements in bone mineral density after successful parathyroidectomy, again raising the issue regarding benefits of surgery. Other randomized studies, however, did not report major gains after surgery.


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InternalMed_Harrison. Cardiovascular disease including left ventricular hypertrophy, carcated PTH fragments were prevented from registering in the newer third-generation assays by use of a detection antibody directed against the extreme amino-terminal epitope. These assays may be useful for clinical research studies as in management of chronic renal disease, but the consensus is that either secondor third-generation assays are useful in the diagnosis of primary hyperparathyroidism and for the diagnosis of high-turnover bone disease in chronic kidney disease. Many tests based on renal responses to excess PTH (renal calcium and phosphate clearance; blood phosphate, chloride, magnesium; urinary or nephrogenous cyclic AMP [cAMP]) were used in earlier decades. These tests have low specificity for hyperparathyroidism and are therefore not cost-effective; they have been replaced by PTH immunometric assays combined with simultaneous blood calcium measurements (Fig. 424-4).


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InternalMed_Harrison. diac functional defects, and endothelial dysfunction have been reported as reversible in European patients with more severe symptomatic disease after surgery, leading to numerous studies of these cardiovascular features in those with milder disease. There are reports of endothelial Surgical excision of the abnormal parathyroid tissue is the defini tive therapy for this disease. As noted above, medical surveillance dysfunction in patients with mild asymptomatic hyperparathyroidism, without operation for patients with mild, asymptomatic disease is, but the expert panels concluded that more observation is needed, espe cially regarding whether there is reversibility with surgery.


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InternalMed_Harrison. A topic of considerable interest and some debate is assessment of neuropsychiatric status and health-related quality of life (QOL) status in hyperparathyroid patients both before surgery and in response to parathyroidectomy. Several observational studies suggest considerable however, still preferred by some physicians and patients, particu larly when the patients are more elderly. Evidence favoring surgery, if medically feasible, is growing because of concerns about skeletal, improvements in symptom score after surgery. Randomized studies 1000 of surgery versus observation, however, have yielded inconclusive results, especially regarding benefits of surgery. Most studies report 800 that hyperparathyroidism is associated with increased neuropsychi-600 atric symptoms, so the issue remains a significant factor in decisions regarding the impact of surgery in this disease. Disorders of the Parathyroid Gland and Calcium Homeostasis


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InternalMed_Harrison. Disorders of the Parathyroid Gland and Calcium Homeostasis The diagnosis is typically made by detecting an elevated immunoreactive PTH level in a patient with asymptomatic hypercalcemia (see “Differential Diagnosis: Special Tests,” below). Serum phosphate is usually low but may be normal, especially if renal failure has developed.


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InternalMed_Harrison. Several modifications in PTH assays have been introduced in efforts to improve their utility in light of information about metabolism of PTH (as discussed above). First-generation assays were based on displacement of radiolabeled PTH from antibodies that reacted with PTH (often also PTH fragments). Double-antibody or immunometric assays (one antibody that is usually directed against the carboxylterminal portion of intact PTH to capture the hormone and a second radioor enzyme-labeled antibody that is usually directed against the amino-terminal portion of intact PTH) greatly improved the diagnostic discrimination of the tests by eliminating interference from aUpdates guidelines (JP Bilezikian et al: J Clin Endocrinol Metab 2014; epub ahead of print). bCreatinine clearance calculated by Cockcroft-Gault equation or Modification of Diet in Renal Disease (MDRD) equation.


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InternalMed_Harrison. FIGURE 424-4 Levels of immunoreactive parathyroid hormone (PTH) detected in patients with primary hyperparathyroidism, hypercalcemia of malignancy, and hypoparathyroidism. Boxed area represents the upper and normal limits of blood calcium and/or immunoreactive PTH. (From SR Nussbaum, JT Potts, Jr, in L DeGroot, JL Jameson [eds]: Endocrinology, 4th ed. Philadelphia, Saunders, 2001; with permission.) 2474 cardiovascular, and neuropsychiatric disease, even in mild hyperparathyroidism. Two surgical approaches are generally practiced. The conventional parathyroidectomy procedure was neck exploration with general anesthesia; this procedure is being replaced in many centers, whenever feasible, by an outpatient procedure with local anesthesia, termed minimally invasive parathyroidectomy. Parathyroid exploration is challenging and should be undertaken by an experienced surgeon. Certain features help in predicting the pathology (e.g., multiple abnormal glands in familial cases). However, some


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InternalMed_Harrison. exploration is challenging and should be undertaken by an experienced surgeon. Certain features help in predicting the pathology (e.g., multiple abnormal glands in familial cases). However, some critical decisions regarding management can be made only during the operation. With conventional surgery, one approach is still based on the view that typically only one gland (the adenoma) is abnormal. If an enlarged gland is found, a normal gland should be sought. In this view, if a biopsy of a normal-sized second gland confirms its histologic (and presumed functional) normality, no further exploration, biopsy, or excision is needed. At the other extreme is the minority viewpoint that all four glands be sought and that most of the total parathyroid tissue mass be removed. The concern with the former approach is that the recurrence rate of hyperparathyroidism may be high if a second abnormal gland is missed; the latter approach could involve unnecessary surgery and an unacceptable rate of


InternalMed_Harrison

InternalMed_Harrison. former approach is that the recurrence rate of hyperparathyroidism may be high if a second abnormal gland is missed; the latter approach could involve unnecessary surgery and an unacceptable rate of hypoparathyroidism. When normal glands are found in association with one enlarged gland, excision of the single adenoma usually leads to cure or at least years free of symptoms. Long-term follow-up studies to establish true rates of recurrence are limited. Recently, there has been growing experience with new surgical strategies that feature a minimally invasive approach guided by improved preoperative localization and intraoperative monitoring by PTH assays. Preoperative 99mTc sestamibi scans with single-photon emission CT (SPECT) are used to predict the location of an abnormal gland and intraoperative sampling of PTH before and at 5-min intervals after removal of a suspected adenoma to confirm a rapid fall (>50%) to normal levels of PTH. In several centers, a combination of preoperative


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InternalMed_Harrison. sampling of PTH before and at 5-min intervals after removal of a suspected adenoma to confirm a rapid fall (>50%) to normal levels of PTH. In several centers, a combination of preoperative sestamibi imaging, cervical block anesthesia, minimal surgical incision, and intraoperative PTH measurements has allowed successful outpatient surgical management with a clear-cut cost benefit compared to general anesthesia and more extensive neck surgery. The use of these minimally invasive approaches requires clinical judgment to select patients unlikely to have multiple gland disease (e.g., MEN or secondary hyperparathyroidism). The growing acceptance of the technique and its relative ease for the patient has lowered the threshold for surgery. Severe hypercalcemia may provide a preoperative clue to the presence of parathyroid carcinoma. In such cases, when neck exploration is undertaken, the tissue should be widely excised; care is taken to avoid rupture of the capsule to prevent local seeding of


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InternalMed_Harrison. presence of parathyroid carcinoma. In such cases, when neck exploration is undertaken, the tissue should be widely excised; care is taken to avoid rupture of the capsule to prevent local seeding of tumor cells. Multiple-gland hyperplasia, as predicted in familial cases, poses more difficult questions of surgical management. Once a diagnosis of hyperplasia is established, all the glands must be identified. Two schemes have been proposed for surgical management. One is to totally remove three glands with partial excision of the fourth gland; care is taken to leave a good blood supply for the remaining gland. Other surgeons advocate total parathyroidectomy with immediate transplantation of a portion of a removed, minced parathyroid gland into the muscles of the forearm, with the view that surgical excision is easier from the ectopic site in the arm if there is recurrent hyperfunction. In a minority of cases, if no abnormal parathyroid glands are found in the neck, the issue of further


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InternalMed_Harrison. surgical excision is easier from the ectopic site in the arm if there is recurrent hyperfunction. In a minority of cases, if no abnormal parathyroid glands are found in the neck, the issue of further exploration must be decided. There are documented cases of five or six parathyroid glands and of unusual locations for adenomas such as in the mediastinum. When a second parathyroid exploration is indicated, the minimally invasive techniques for preoperative localization such as ultrasound, CT scan, and isotope scanning are combined with venous sampling and/or selective digital arteriography in one of the centers specializing in these procedures. Intraoperative monitoring of PTH levels by rapid PTH immunoassays may be useful in guiding the surgery. At one center, long-term cures have been achieved with selective embolization or injection of large amounts of contrast material into the end-arterial circulation feeding the parathyroid tumor.


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InternalMed_Harrison. A decline in serum calcium occurs within 24 h after successful surgery; usually blood calcium falls to low-normal values for 3–5 days until the remaining parathyroid tissue resumes full hormone secretion. Acute postoperative hypocalcemia is likely only if severe bone mineral deficits are present or if injury to all the normal parathyroid glands occurs during surgery. In general, there are few problems encountered in patients with uncomplicated disease such as a single adenoma (the clear majority), who do not have symptomatic bone disease or a large deficit in bone mineral, who are vitamin D and magnesium sufficient, and who have good renal and gastrointestinal function. The extent of postoperative hypocalcemia varies with the surgical approach. If all glands are biopsied, hypocalcemia may be transiently symptomatic and more prolonged. Hypocalcemia is more likely to be symptomatic after second parathyroid explorations, particularly when normal parathyroid tissue was removed at the


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InternalMed_Harrison. may be transiently symptomatic and more prolonged. Hypocalcemia is more likely to be symptomatic after second parathyroid explorations, particularly when normal parathyroid tissue was removed at the initial operation and when the manipulation and/or biopsy of the remaining normal glands are more extensive in the search for the missing adenoma.


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InternalMed_Harrison. Patients with hyperparathyroidism have efficient intestinal calcium absorption due to the increased levels of 1,25(OH)2D stimulated by PTH excess. Once hypocalcemia signifies successful surgery, patients can be put on a high-calcium intake or be given oral calcium supplements. Despite mild hypocalcemia, most patients do not require parenteral therapy. If the serum calcium falls to <2 mmol/L (8 mg/dL), and if the phosphate level rises simultaneously, the possibility that surgery has caused hypoparathyroidism must be considered. With unexpected hypocalcemia, coexistent hypomagnesemia should be considered, because it interferes with PTH secretion and causes functional hypoparathyroidism (Chap. 423).


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InternalMed_Harrison. Signs of hypocalcemia include symptoms such as muscle twitching, a general sense of anxiety, and positive Chvostek’s and Trousseau’s signs coupled with serum calcium consistently <2 mmol/L (8 mg/dL). Parenteral calcium replacement at a low level should be instituted when hypocalcemia is symptomatic. The rate and duration of IV therapy are determined by the severity of the symptoms and the response of the serum calcium to treatment. An infusion of 0.5–2 mg/kg per hour or 30–100 mL/h of a 1-mg/mL solution usually suffices to relieve symptoms. Usually, parenteral therapy is required for only a few days. If symptoms worsen or if parenteral calcium is needed for >2–3 days, therapy with a vitamin D analogue and/or oral calcium (2–4 g/d) should be started (see below). It is cost-effective to use calcitriol (doses of 0.5–1 μg/d) because of the rapidity of onset of effect and prompt cessation of action when stopped, in comparison to other forms of vitamin D. A rise in blood calcium after


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InternalMed_Harrison. use calcitriol (doses of 0.5–1 μg/d) because of the rapidity of onset of effect and prompt cessation of action when stopped, in comparison to other forms of vitamin D. A rise in blood calcium after several months of vitamin D replacement may indicate restoration of parathyroid function to normal. It is also appropriate to monitor serum PTH serially to estimate gland function in such patients.


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InternalMed_Harrison. If magnesium deficiency was present, it can complicate the postoperative course since magnesium deficiency impairs the secretion of PTH. Hypomagnesemia should be corrected whenever detected. Magnesium replacement can be effective orally (e.g., MgCl2, MgOH2), but parenteral repletion is usual to ensure postoperative recovery, if magnesium deficiency is suspected due to low blood magnesium levels. Because the depressant effect of magnesium on central and peripheral nerve functions does not occur at levels <2 mmol/L (normal range 0.8–1.2 mmol/L), parenteral replacement can be given rapidly. A cumulative dose as great as 0.5–1 mmol/kg of body weight can be administered if severe hypomagnesemia is present; often, however, total doses of 20–40 mmol are sufficient.


InternalMed_Harrison

InternalMed_Harrison. The guidelines for recommending surgical intervention, if feasible (Table 424-2), as well as for monitoring patients with asymptomatic hyperparathyroidism who elect not to undergo parathyroidectomy (Table 424-3), reflect the changes over time since the first conference on the topic in 1990. Medical monitoring rather than corrective surgery is still acceptable, but it is clear that surgical intervention is the more frequently recommended option for the reasons noted above. Tightened guidelines favoring surgery include lowering the recommended level of serum calcium elevation, more careful attention to skeletal integrity through reference to peak skeletal mass at baseline (T scores) rather than age-adjusted bone density (Z scores), as well as the presence of any fragility fracture. The other changes noted in the two guidelines (Tables 424-2 and 424-3) reflect accumulated experience and practical consideration, such as a difficulty in quantity of urine collections. Despite the usefulness


InternalMed_Harrison

InternalMed_Harrison. changes noted in the two guidelines (Tables 424-2 and 424-3) reflect accumulated experience and practical consideration, such as a difficulty in quantity of urine collections. Despite the usefulness of the guidelines, the importance of individual patient and physician judgment and preference is clear in all recommendations.


InternalMed_Harrison

InternalMed_Harrison. When surgery is not selected, or not medically feasible, there is interest in the potential value of specific medical therapies. There is no long-term experience regarding specific clinical outcomes such as fracture prevention, but it has been established that bisphosphonates increase bone mineral density significantly without changing serum calcium (as does estrogen, but the latter is not favored because of reported adverse effects in other organ systems). Calcimimetics that lower PTH secretion lower calcium but do not affect bone mineral density.


InternalMed_Harrison

InternalMed_Harrison. OTHER PARATHYROID-RELATED CAUSES OF HYPERCALCEMIA Lithium Therapy Lithium, used in the management of bipolar depression and other psychiatric disorders, causes hypercalcemia in ~10% of treated patients. The hypercalcemia is dependent on continued lithium treatment, remitting and recurring when lithium is stopped and restarted. The parathyroid adenomas reported in some hypercalcemic patients with lithium therapy may reflect the presence of an independently occurring parathyroid tumor; a permanent effect of lithium on parathyroid gland growth need not be implicated as most patients have complete reversal of hypercalcemia when lithium is stopped. However, long-standing stimulation of parathyroid cell replication by lithium may predispose to development of adenomas (as is documented in secondary hyperparathyroidism and renal failure).


InternalMed_Harrison

InternalMed_Harrison. At the levels achieved in blood in treated patients, lithium can be shown in vitro to shift the PTH secretion curve to the right in response to calcium; i.e., higher calcium levels are required to lower PTH secretion, probably acting at the calcium sensor (see below). This effect can cause elevated PTH levels and consequent hypercalcemia in otherwise normal individuals. Fortunately, there are usually alternative medications for the underlying psychiatric illness. Parathyroid surgery should not be recommended unless hypercalcemia and elevated PTH levels persist after lithium is discontinued.


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InternalMed_Harrison. GENETIC DISORDERS CAUSING HYPERPARATHYROID-LIKE SYNDROMES Familial Hypocalciuric Hypercalcemia FHH (also called familial benign hypercalcemia) is inherited as an autosomal dominant trait. Affected individuals are discovered because of asymptomatic hypercalcemia. Most cases of FHH (FHH1) are caused by an inactivating mutation in a single allele of the CaSR (see below), leading to inappropriately normal or even increased secretion of PTH, whereas another hypercalcemic disorder, namely the exceedingly rare Jansen’s disease, is caused by a constitutively active PTH/PTHrP receptor in target tissues. Neither FHH1 nor Jansen’s disease, however, is a growth disorder of the parathyroids. Other forms of FHH are caused either by heterozygous mutations in GNA11 (encoding G11), one of the signaling proteins downstream of the CaSR (FHH2), or by mutations in AP2S1 (FHH3).


InternalMed_Harrison

InternalMed_Harrison. The pathophysiology of FHH1 is now understood. The primary defect is abnormal sensing of the blood calcium by the parathyroid gland and renal tubule, causing inappropriate secretion of PTH and excessive reabsorption of calcium in the distal renal tubules. The CaSR is a member of the third family of GPCRs (type C or type III). The receptor responds to increased ECF calcium concentration by suppressing PTH secretion through second-messenger signaling involving the G protein alpha-subunits G11 and Gq, thereby providing negative-feedback regulation of PTH secretion. Many different inac-2475 tivating CaSR mutations have been identified in patients with FHH1. These mutations lower the capacity of the sensor to bind calcium, and the mutant receptors function as though blood calcium levels were low; excessive secretion of PTH occurs from an otherwise normal gland. Approximately two-thirds of patients with FHH have mutations within the protein-coding region of the CaSR gene. The remaining


InternalMed_Harrison

InternalMed_Harrison. low; excessive secretion of PTH occurs from an otherwise normal gland. Approximately two-thirds of patients with FHH have mutations within the protein-coding region of the CaSR gene. The remaining one-third of kindreds may have mutations in the promoter of the CaSR gene or are caused by mutations in other genes.


InternalMed_Harrison

InternalMed_Harrison. Even before elucidation of the pathophysiology of FHH, abundant clinical evidence served to separate the disorder from primary hyperparathyroidism; these clinical features are still useful in differential diagnosis. Patients with primary hyperparathyroidism have <99% renal calcium reabsorption, whereas most patients with FHH have >99% reabsorption. The hypercalcemia in FHH is often detectable in affected members of the kindreds in the first decade of life, whereas hypercalcemia rarely occurs in patients with primary hyperparathyroidism or the MEN syndromes who are age <10 years. PTH may be elevated in the different forms of FHH, but the values are usually normal or lower for the same degree of calcium elevation than is observed in patients with primary hyperparathyroidism. Parathyroid surgery performed in a few patients with FHH before the nature of the syndrome was understood led to permanent hypoparathyroidism; nevertheless, hypocalciuria persisted, establishing that hypocalciuria


InternalMed_Harrison

InternalMed_Harrison. performed in a few patients with FHH before the nature of the syndrome was understood led to permanent hypoparathyroidism; nevertheless, hypocalciuria persisted, establishing that hypocalciuria is not PTH-dependent (now known to be due to the abnormal CaSR in the kidney).


InternalMed_Harrison

InternalMed_Harrison. Few clinical signs or symptoms are present in patients with FHH, whereas other endocrine abnormalities are not. Most patients are detected as a result of family screening after hypercalcemia is detected in a proband. In those patients inadvertently operated upon for primary hyperparathyroidism, the parathyroids appeared normal or moderately hyperplastic. Parathyroid surgery is not appropriate, nor, in view of the lack of symptoms, does medical treatment seem needed to lower the calcium. One striking exception to the rule against parathyroid surgery in this syndrome is the occurrence, usually in consanguineous marriages (due to the rarity of the gene mutation), of a homozygous or compound heterozygote state, resulting in severe impairment of CaSR function. In this condition, neonatal severe hypercalcemia, total parathyroidectomy is mandatory, but calcimetics have been used as a temporary measure. Rare but well-documented cases of acquired hypocalciuric hypercalcemia are reported due to


InternalMed_Harrison

InternalMed_Harrison. hypercalcemia, total parathyroidectomy is mandatory, but calcimetics have been used as a temporary measure. Rare but well-documented cases of acquired hypocalciuric hypercalcemia are reported due to antibodies against the CaSR. They appear to be a complication of an underlying autoimmune disorder and respond to therapies directed against the underlying disorder.


InternalMed_Harrison

InternalMed_Harrison. Jansen’s Disease Activating mutations in the PTH/PTHrP receptor (PTH1R) have been identified as the cause of this rare autosomal dominant syndrome. Because the mutations lead to constitutive activation of receptor function, one abnormal copy of the mutant receptor is sufficient to cause the disease, thereby accounting for its dominant mode of transmission. The disorder leads to short-limbed dwarfism due to abnormal regulation of chondrocyte maturation in the growth plates of the bone that are formed through the endochondral process. In adult life, there are numerous abnormalities in bone, including multiple cystic resorptive areas resembling those seen in severe hyperparathyroidism. Hypercalcemia and hypophosphatemia with undetectable or low PTH levels are typically observed. The pathogenesis of the growth plate abnormalities in Jansen’s disease has been confirmed by transgenic experiments in which targeted expression of the mutant PTH/PTHrP receptor to the proliferating chondrocyte


InternalMed_Harrison

InternalMed_Harrison. of the growth plate abnormalities in Jansen’s disease has been confirmed by transgenic experiments in which targeted expression of the mutant PTH/PTHrP receptor to the proliferating chondrocyte layer of growth plate emulated several features of the human disorder. Some of these genetic mutations in the parathyroid gland or PTH target cells that affect Ca2+ metabolism are illustrated in Fig. 424-5.


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InternalMed_Harrison. MALIGNANCY-RELATED HYPERCALCEMIA Clinical Syndromes and Mechanisms of Hypercalcemia Hypercalcemia due to malignancy is common (occurring in as many as 20% of cancer patients, especially with certain types of tumor such as lung carcinoma), often severe and difficult to manage, and, on rare occasions, Disorders of the Parathyroid Gland and Calcium Homeostasis Loss-of-function FHH1, Blomstrand’s lethal NSHPT chondrodysplasia C Cellular events, RC R including HDAC4 Transcription factors, e.g. GATA3, GCM2, AIRE, FAM111A Gq/11 IP3 + DAG Acrodysostosis with (e.g. kidney, bone, or cartilage)


InternalMed_Harrison

InternalMed_Harrison. FIGURE 424-5 Illustration of some genetic mutations that alter calcium metabolism by effects on the parathyroid cell or target cells of parathyroid hormone (PTH) action. Alterations in PTH production by the parathyroid cell can be caused by changes in the response to extracellular fluid calcium (Ca2+) that are detected by the calcium-sensing receptor (CaSR). Furthermore, PTH (or PTH-related peptide [PTHrP]) can show altered efficacy in target cells such as in proximal tubular cells, by altered function of its receptor (PTH/PTHrP receptor) or the signal transduction proteins, G proteins such as Gsα, which is linked to adenylate cyclase (AC), the enzyme responsible for producing cyclic AMP (cAMP) (also illustrated are Gq/11, which activate an alternate pathway of receptor signal transmission involving the generation of inositol triphosphate [IP3] or diacylglycerol [DAG]). Heterozygous loss-of-function mutations in the CaSR cause familial benign hypocalciuric hypercalcemia (FBHH),


InternalMed_Harrison

InternalMed_Harrison. involving the generation of inositol triphosphate [IP3] or diacylglycerol [DAG]). Heterozygous loss-of-function mutations in the CaSR cause familial benign hypocalciuric hypercalcemia (FBHH), homozygous mutations (both alleles mutated), and severe neonatal hyperparathyroidism (NSHPT); heterozygous gain-of-function causes autosomal dominant hypercalciuric hypocalcemia (ADHH). Other defects in parathyroid cell function that occur at the level of gene regulation (oncogenes or tumor-suppressor genes) or transcription factors are discussed in the text. Blomstrand’s lethal chondrodysplasia is due to homozygous or compound heterozygous loss-of-function mutations in the PTH/PTHrP receptor, a neonatally lethal disorder, while pseudohypoparathyroidism involves inactivation at the level of the G proteins, specifically mutations that eliminate or reduce Gsα activity in the kidney (see text for details). Acrodysostosis can occur with (acrodysostosis with hormonal resistance [ADOHR]; mutant


InternalMed_Harrison

InternalMed_Harrison. G proteins, specifically mutations that eliminate or reduce Gsα activity in the kidney (see text for details). Acrodysostosis can occur with (acrodysostosis with hormonal resistance [ADOHR]; mutant regulatory subunit of PKA) or without hormonal resistance (ADOP4; mutant PDE4D). Jansen’s metaphyseal chondrodysplasia and McCune-Albright syndrome represent gain-of-function mutations in the PTH/PTHrP receptor and Gsα protein, respectively.


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InternalMed_Harrison. difficult to distinguish from primary hyperparathyroidism. Although produced by activated normal lymphocytes and by myeloma and malignancy is often clinically obvious or readily detectable by medical lymphoma cells, originally termed osteoclast activation factor, now history, hypercalcemia can occasionally be due to an occult tumor. appears to represent the biologic action of several different cytokines, Previously, hypercalcemia associated with malignancy was thought to probably interleukin 1 and lymphotoxin or tumor necrosis factor be due to local invasion and destruction of bone by tumor cells; many (TNF). In some lymphomas, there is a third mechanism, caused by cases are now known to result from the elaboration by the malignant an increased blood level of 1,25(OH)2D, produced by the abnormal cells of humoral mediators of hypercalcemia. PTHrP is the responsible lymphocytes. humoral agent in most solid tumors that cause hypercalcemia. In the more common mechanism, usually termed


InternalMed_Harrison

InternalMed_Harrison. abnormal cells of humoral mediators of hypercalcemia. PTHrP is the responsible lymphocytes. humoral agent in most solid tumors that cause hypercalcemia. In the more common mechanism, usually termed humoral hyper-


InternalMed_Harrison

InternalMed_Harrison. The histologic character of the tumor is more important than the calcemia of malignancy, solid tumors (cancers of the lung and kidney, extent of skeletal metastases in predicting hypercalcemia. Small-cell in particular), in which bone metastases are absent, minimal, or not carcinoma (oat cell) and adenocarcinoma of the lung, although the detectable clinically, secrete PTHrP measurable by immunoassay. most common lung tumors associated with skeletal metastases, rarely Secretion by the tumors of the PTH-like factor, PTHrP, activates the cause hypercalcemia. By contrast, many patients with squamous cell PTH1R, resulting in a pathophysiology closely resembling hyperparacarcinoma of the lung develop hypercalcemia. Histologic studies of thyroidism, but with normal or suppressed PTH levels. The clinical bone in patients with squamous cell or epidermoid carcinoma of the picture resembles primary hyperparathyroidism (hypophosphatemia lung, in sites invaded by tumor as well as areas remote from


InternalMed_Harrison

InternalMed_Harrison. bone in patients with squamous cell or epidermoid carcinoma of the picture resembles primary hyperparathyroidism (hypophosphatemia lung, in sites invaded by tumor as well as areas remote from tumor accompanies hypercalcemia), and elimination or regression of the invasion, reveal increased bone resorption. primary tumor leads to disappearance of the hypercalcemia.


InternalMed_Harrison

InternalMed_Harrison. Two main mechanisms of hypercalcemia are operative in cancer As in hyperparathyroidism, patients with the humoral hypercalcehypercalcemia. Many solid tumors associated with hypercalcemia, mia of malignancy have elevated urinary nephrogenous cAMP excreparticularly squamous cell and renal tumors, produce and secrete tion, hypophosphatemia, and increased urinary phosphate clearance. PTHrP that causes increased bone resorption and mediate the hyper-However, in humoral hypercalcemia of malignancy, immunoreactive calcemia through systemic actions on the skeleton. Alternatively, PTH is undetectable or suppressed, making the differential diagnosis direct bone marrow invasion occurs with hematologic malignancies easier. Other features of the disorder differ from those of true hyper-such as leukemia, lymphoma, and multiple myeloma. Lymphokines parathyroidism. Although the biologic actions of PTH and PTHrP and cytokines (including PTHrP) produced by cells involved in are exerted through the same


InternalMed_Harrison

InternalMed_Harrison. lymphoma, and multiple myeloma. Lymphokines parathyroidism. Although the biologic actions of PTH and PTHrP and cytokines (including PTHrP) produced by cells involved in are exerted through the same receptor, subtle differences in receptor the marrow response to the tumors promote resorption of bone activation by the two ligands must account for some of the discordance through local destruction. Several hormones, hormone analogues, in pathophysiology, when an excess of one or the other peptide occurs. cytokines, and growth factors have been implicated as the result of Other cytokines elaborated by the malignancy may contribute to the clinical assays, in vitro tests, or chemical isolation. The etiologic factor variations from hyperparathyroidism in these patients as well. Patients with humoral hypercalcemia of malignancy may have low to normal levels of 1,25(OH)2D instead of elevated levels as in true hyperparathyroidism. In some patients with the humoral hypercalcemia of malignancy,


InternalMed_Harrison

InternalMed_Harrison. hypercalcemia of malignancy may have low to normal levels of 1,25(OH)2D instead of elevated levels as in true hyperparathyroidism. In some patients with the humoral hypercalcemia of malignancy, osteoclastic resorption is unaccompanied by an osteoblastic or bone-forming response, implying inhibition of the normal coupling of bone formation and resorption.


InternalMed_Harrison

InternalMed_Harrison. Several different assays (singleor double-antibody, different epitopes) have been developed to detect PTHrP. Most data indicate that circulating PTHrP levels are undetectable (or low) in normal individuals except perhaps in pregnancy (high in human milk) and elevated in most cancer patients with the humoral syndrome. The etiologic mechanisms in cancer hypercalcemia may be multiple in the same patient. For example, in breast carcinoma (metastatic to bone) and in a distinctive type of T cell lymphoma/leukemia initiated by human T cell lymphotropic virus I, hypercalcemia is caused by direct local lysis of bone as well as by a humoral mechanism involving excess production of PTHrP. Hyperparathyroidism has been reported to coexist with the humoral cancer syndrome, and rarely, ectopic hyperparathyroidism due to tumor elaboration of true PTH is reported.


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InternalMed_Harrison. Diagnostic Issues Levels of PTH measured by the double-antibody technique are undetectable or extremely low in tumor hypercalcemia, as would be expected with the mediation of the hypercalcemia by a factor other than PTH (the hypercalcemia suppresses the normal parathyroid glands). In a patient with minimal symptoms referred for hypercalcemia, low or undetectable PTH levels would focus attention on a possible occult malignancy (except for very rare cases of ectopic hyperparathyroidism).


InternalMed_Harrison

InternalMed_Harrison. Ordinarily, the diagnosis of cancer hypercalcemia is not difficult because tumor symptoms are prominent when hypercalcemia is detected. Indeed, hypercalcemia may be noted incidentally during the workup of a patient with known or suspected malignancy. Clinical suspicion that malignancy is the cause of the hypercalcemia is heightened when there are other signs or symptoms of a paraneoplastic process such as weight loss, fatigue, muscle weakness, or unexplained skin rash, or when symptoms specific for a particular tumor are present. Squamous cell tumors are most frequently associated with hypercalcemia, particularly tumors of the lung, kidney, head and neck, and urogenital tract. Radiologic examinations can focus on these areas when clinical evidence is unclear. Bone scans with technetium-labeled bisphosphonate are useful for detection of osteolytic metastases; the sensitivity is high, but specificity is low; results must be confirmed by conventional x-rays to be certain that areas of


InternalMed_Harrison

InternalMed_Harrison. bisphosphonate are useful for detection of osteolytic metastases; the sensitivity is high, but specificity is low; results must be confirmed by conventional x-rays to be certain that areas of increased uptake are due to osteolytic metastases per se. Bone marrow biopsies are helpful in patients with anemia or abnormal peripheral blood smears.


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InternalMed_Harrison. Treatment of the hypercalcemia of malignancy is first directed to control of tumor; reduction of tumor mass usually corrects hypercalcemia. If a patient has severe hypercalcemia yet has a good chance for effective tumor therapy, treatment of the hypercalcemia should be vigorous while awaiting the results of definitive therapy. If hypercalcemia occurs in the late stages of a tumor that is resistant to antitumor therapy, the treatment of the hypercalcemia should be judicious as high calcium levels can have a mild sedating effect. Standard therapies for hypercalcemia (discussed below) are applicable to patients with malignancy.


InternalMed_Harrison

InternalMed_Harrison. Hypercalcemia caused by vitamin D can be due to excessive ingestion or abnormal metabolism of the vitamin. Abnormal metabolism of the vitamin is usually acquired in association with a widespread granulomatous disorder. Vitamin D metabolism is carefully regulated, particularly the activity of renal 1α-hydroxylase, the enzyme responsible for the production of 1,25(OH)2D (Chap. 423). The regulation of 1α-hydroxylase and the normal feedback suppression by 1,25(OH)2D 2477 seem to work less well in infants than in adults and to operate poorly, if at all, in sites other than the renal tubule; these phenomena may explain the occurrence of hypercalcemia secondary to excessive 1,25(OH)2D production in infants with Williams’ syndrome (see below) and in adults with sarcoidosis or lymphoma.


InternalMed_Harrison

InternalMed_Harrison. Vitamin D Intoxication Chronic ingestion of 40–100 times the normal physiologic requirement of vitamin D (amounts >40,000–100,000 U/d) is usually required to produce significant hypercalcemia in otherwise healthy individuals. The stated upper limit of safe dietary intake is 2000 U/d (50 μg/d) in adults because of concerns about potential toxic effects of cumulative supraphysiologic doses. These recommendations are now regarded as too restrictive, because some estimates are that in elderly individuals in northern latitudes, 2000 U/d or more may be necessary to avoid vitamin D insufficiency.


InternalMed_Harrison

InternalMed_Harrison. Hypercalcemia in vitamin D intoxication is due to an excessive biologic action of the vitamin, perhaps the consequence of increased levels of 25(OH)D rather than merely increased levels of the active metabolite 1,25(OH)2D (the latter may not be elevated in vitamin D intoxication). 25(OH)D has definite, if low, biologic activity in the intestine and bone. The production of 25(OH)D is less tightly regulated than is the production of 1,25(OH)2D. Hence concentrations of 25(OH)D are elevated several-fold in patients with excess vitamin D intake. The diagnosis is substantiated by documenting elevated levels of 25(OH)D >100 mg/mL. Hypercalcemia is usually controlled by restriction of dietary calcium intake and appropriate attention to hydration.


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InternalMed_Harrison. These measures, plus discontinuation of vitamin D, usually lead to resolution of hypercalcemia. However, vitamin D stores in fat may be substantial, and vitamin D intoxication may persist for weeks after vitamin D ingestion is terminated. Such patients are responsive to glucocorticoids, which in doses of 100 mg/d of hydrocortisone or its equivalent usually return serum calcium levels to normal over several days; severe intoxication may require intensive therapy.


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InternalMed_Harrison. Sarcoidosis and Other Granulomatous Diseases In patients with sarcoid osis and other granulomatous diseases, such as tuberculosis and fungal infections, excess 1,25(OH)2D is synthesized in macrophages or other cells in the granulomas. Indeed, increased 1,25(OH)2D levels have been reported in anephric patients with sarcoidosis and hypercalcemia. Macrophages obtained from granulomatous tissue convert 25(OH)D to 1,25(OH)2D at an increased rate. There is a positive correlation in patients with sarcoidosis between 25(OH)D levels (reflecting vitamin D intake) and the circulating concentrations of 1,25(OH)2D, whereas normally there is no increase in 1,25(OH)2D with increasing 25(OH) D levels due to multiple feedback controls on renal 1α-hydroxylase (Chap. 423). The usual regulation of active metabolite production by calcium and phosphate or by PTH does not operate in these patients. Clearance of 1,25(OH)2D from blood may be decreased in sarcoidosis as well. PTH levels are usually low and


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InternalMed_Harrison. metabolite production by calcium and phosphate or by PTH does not operate in these patients. Clearance of 1,25(OH)2D from blood may be decreased in sarcoidosis as well. PTH levels are usually low and 1,25(OH)2D levels are elevated, but primary hyperparathyroidism and sarcoidosis may coexist in some patients.


InternalMed_Harrison

InternalMed_Harrison. Management of the hypercalcemia can often be accomplished by avoiding excessive sunlight exposure and limiting vitamin D and calcium intake. Presumably, however, the abnormal sensitivity to vitamin D and abnormal regulation of 1,25(OH)2D synthesis will persist as long as the disease is active. Alternatively, glucocorticoids in the equivalent of 100 mg/d of hydrocortisone or equivalent doses of glucocorticoids may help control hypercalcemia. Glucocorticoids appear to act by blocking excessive production of 1,25(OH)2D, as well as the response to it in target organs. Idiopathic Hypercalcemia of Infancy This rare disorder, usually referred to as Williams’ syndrome, is an autosomal dominant disorder characterized by multiple congenital development defects, including supravalvular aortic stenosis, mental retardation, and an elfin facies, in association with hypercalcemia due to abnormal sensitivity to vitamin


InternalMed_Harrison

InternalMed_Harrison. D. The hypercalcemia associated with the syndrome was first recognized in England after fortification of milk with vitamin D. The cardiac and developmental abnormalities were independently described, Disorders of the Parathyroid Gland and Calcium Homeostasis 2478 but the connection between these defects and hypercalcemia were not described until later. Levels of 1,25(OH)2D can be elevated, ranging from 46 to 120 nmol/L (150–500 pg/mL). The mechanism of the abnormal sensitivity to vitamin D and of the increased circulating levels of 1,25(OH)2D is still unclear. Studies suggest that genetic mutations involving microdeletions at the elastin locus and perhaps other genes on chromosome 7 may play a role in the pathogenesis. Another cause of hypercalcemia in infants and young children is a 24-hydroxylase deficiency that impairs metabolism of 1,25(OH)2D.


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InternalMed_Harrison. HYPERCALCEMIA ASSOCIATED WITH HIGH BONE TURNOVER Hyperthyroidism As many as 20% of hyperthyroid patients have high-normal or mildly elevated serum calcium concentrations; hypercalciuria is even more common. The hypercalcemia is due to increased bone turnover, with bone resorption exceeding bone formation. Severe calcium elevations are not typical, and the presence of such suggests a concomitant disease such as hyperparathyroidism. Usually, the diagnosis is obvious, but signs of hyperthyroidism may occasionally be occult, particularly in the elderly (Chap. 405). Hypercalcemia is managed by treatment of the hyperthyroidism. Reports that thyroid-stimulating hormone (TSH) itself normally has a bone-protective effect suggest that suppressed TSH levels also play a role in hypercalcemia.


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InternalMed_Harrison. Immobilization Immobilization is a rare cause of hypercalcemia in adults in the absence of an associated disease but may cause hypercalcemia in children and adolescents, particularly after spinal cord injury and paraplegia or quadriplegia. With resumption of ambulation, the hypercalcemia in children usually returns to normal. The mechanism appears to involve a disproportion between bone formation and bone resorption; the former decreased and the latter increased. Hypercalciuria and increased mobilization of skeletal calcium can develop in normal volunteers subjected to extensive bed rest, although hypercalcemia is unusual. Immobilization of an adult with a disease associated with high bone turnover, however, such as Paget’s disease, may cause hypercalcemia.


InternalMed_Harrison

InternalMed_Harrison. Thiazides Administration of benzothiadiazines (thiazides) can cause hypercalcemia in patients with high rates of bone turnover. Traditionally, thiazides are associated with aggravation of hypercalcemia in primary hyperparathyroidism, but this effect can be seen in other high-boneturnover states as well. The mechanism of thiazide action is complex. Chronic thiazide administration leads to reduction in urinary calcium; the hypocalciuric effect appears to reflect the enhancement of proximal tubular resorption of sodium and calcium in response to sodium depletion. Some of this renal effect is due to augmentation of PTH action and is more pronounced in individuals with intact PTH secretion. However, thiazides cause hypocalciuria in hypoparathyroid patients on high-dose vitamin D and oral calcium replacement if sodium intake is restricted. This finding is the rationale for the use of thiazides as an adjunct to therapy in hypoparathyroid patients, as discussed below. Thiazide administration


InternalMed_Harrison

InternalMed_Harrison. replacement if sodium intake is restricted. This finding is the rationale for the use of thiazides as an adjunct to therapy in hypoparathyroid patients, as discussed below. Thiazide administration to normal individuals causes a transient increase in blood calcium (usually within the high-normal range) that reverts to preexisting levels after a week or more of continued administration. If hormonal function and calcium and bone metabolism are normal, homeostatic controls are reset to counteract the calcium-elevating effect of the thiazides. In the presence of hyperparathyroidism or increased bone turnover from another cause, homeostatic mechanisms are ineffective. The abnormal effects of the thiazide on calcium metabolism disappear within days of cessation of the drug.


InternalMed_Harrison

InternalMed_Harrison. Vitamin A Intoxication Vitamin A intoxication is a rare cause of hypercalcemia and is most commonly a side effect of dietary faddism (Chap. 96e). Calcium levels can be elevated into the 3–3.5-mmol/L (12–14 mg/dL) range after the ingestion of 50,000–100,000 units of vitamin A daily (10–20 times the minimum daily requirement). Typical features of severe hypercalcemia include fatigue, anorexia, and, in some, severe muscle and bone pain. Excess vitamin A intake is presumed to increase bone resorption. The diagnosis can be established by history and by measurement of vitamin A levels in serum. Occasionally, skeletal x-rays reveal periosteal calcifications, particularly in the hands. Withdrawal of the vitamin is usually associated with prompt disappearance of the hypercalcemia and reversal of the skeletal changes. As in vitamin D intoxication, administration of 100 mg/d of hydrocortisone or its equivalent leads to a rapid return of the serum calcium to normal.


InternalMed_Harrison

InternalMed_Harrison. HYPERCALCEMIA ASSOCIATED WITH RENAL FAILURE Severe Secondary Hyperparathyroidism The pathogenesis of secondary hyperparathyroidism in chronic kidney disease is incompletely understood. Resistance to the normal level of PTH is a major factor contributing to the development of hypocalcemia, which, in turn, is a stimulus to parathyroid gland enlargement. However, recent findings have indicated that an increase of FGF23 production by osteocytes (and possibly osteoblasts) in bone occurs well before an elevation in PTH is detected. FGF23 is a potent inhibitor of the renal 1-alpha hydroxylase, and the FGF23-dependent reduction in 1,25(OH)2 vitamin D seems to be an important stimulus for the development of secondary hyperparathyroidism.


InternalMed_Harrison

InternalMed_Harrison. Secondary hyperparathyroidism occurs not only in patients with renal failure but also in those with osteomalacia due to multiple causes (Chap. 423), including deficiency of vitamin D action and pseudohypoparathyroidism (deficient response to PTH downstream of PTHR1). For both disorders, hypocalcemia seems to be the common denominator in initiating the development of secondary hyperparathyroidism. Primary (1°) and secondary (2°) hyperparathyroidism can be distinguished conceptually by the autonomous growth of the parathyroid glands in primary hyperparathyroidism (presumably irreversible) and the adaptive response of the parathyroids in secondary hyperparathyroidism (typically reversible). In fact, reversal over weeks from an abnormal pattern of secretion, presumably accompanied by involution of parathyroid gland mass to normal, occurs in patients with osteomalacia who have been treated effectively with calcium and vitamin D. However, it is now recognized that a true clonal outgrowth


InternalMed_Harrison

InternalMed_Harrison. of parathyroid gland mass to normal, occurs in patients with osteomalacia who have been treated effectively with calcium and vitamin D. However, it is now recognized that a true clonal outgrowth (irreversible) can arise in long-standing, inadequately treated chronic kidney disease (e.g., tertiary [3°] hyperparathyroidism; see below).


InternalMed_Harrison

InternalMed_Harrison. Patients with secondary hyperparathyroidism may develop bone pain, ectopic calcification, and pruritus. The bone disease seen in patients with secondary hyperparathyroidism and chronic kidney disease is termed renal osteodystrophy and affects primarily bone turnover. However, osteomalacia is frequently encountered as well and may be related to the circulating levels of FGF23.


InternalMed_Harrison

InternalMed_Harrison. Two other skeletal disorders have been frequently associated in the past with chronic kidney disease (CKD) patients treated by longterm dialysis, who received aluminum-containing phosphate binders. Aluminum deposition in bone (see below) leads to an osteomalacialike picture. The other entity is a low-turnover bone disease termed “aplastic” or “adynamic” bone disease; PTH levels are lower than typically observed in CKD patients with secondary hyperparathyroidism. It is believed that the condition is caused, at least in part, by excessive PTH suppression, which may be even greater than previously appreciated in light of evidence that some of the immunoreactive PTH detected by most commercially available PTH assays is not the full-length biologically active molecule (as discussed above) but may consist of amino-terminally truncated fragments that do not activate the PTH1R.


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InternalMed_Harrison. Medical therapy to reverse secondary hyperparathyroidism in CKD includes reduction of excessive blood phosphate by restriction of dietary phosphate, the use of nonabsorbable phosphate binders, and careful, selective addition of calcitriol (0.25–2 μg/d) or related analogues. Calcium carbonate became preferred over aluminum-containing antacids to prevent aluminum-induced bone disease. However, synthetic gels that also bind phosphate (such as sevelamer; Chap. 335) are now widely used, with the advantage of avoiding not only aluminum retention, but also excess calcium loading, which may contribute to cardiovascular calcifications. Intravenous calcitriol (or related analogues), administered as several pulses each week, helps control secondary hyperparathyroidism. Aggressive but carefully administered medical therapy can often, but not always, reverse hyperparathyroidism and its symptoms and manifestations.


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InternalMed_Harrison. Occasional patients develop severe manifestations of secondary hyperparathyroidism, including hypercalcemia, pruritus, extraskeletal calcifications, and painful bones, despite aggressive medical efforts to suppress the hyperparathyroidism. PTH hypersecretion no longer responsive to medical therapy, a state of severe hyperparathyroidism in patients with CKD that requires surgery, has been referred to as tertiary hyperparathyroidism. Parathyroid surgery is necessary to control this condition. Based on genetic evidence from examination of tumor samples in these patients, the emergence of autonomous parathyroid function is due to a monoclonal outgrowth of one or more previously hyperplastic parathyroid glands. The adaptive response has become an independent contributor to disease; this finding seems to emphasize the importance of optimal medical management to reduce the proliferative response of the parathyroid cells that enables the irreversible genetic change.


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InternalMed_Harrison. Aluminum Intoxication Aluminum intoxication (and often hypercalcemia as a complication of medical treatment) in the past occurred in patients on chronic dialysis; manifestations included acute dementia and unresponsive and severe osteomalacia. Bone pain, multiple non-healing fractures, particularly of the ribs and pelvis, and a proximal myopathy occur. Hypercalcemia develops when these patients are treated with vitamin D or calcitriol because of impaired skeletal responsiveness. Aluminum is present at the site of osteoid mineralization, osteoblastic activity is minimal, and calcium incorporation into the skeleton is impaired. The disorder is now rare because of the avoidance of aluminum-containing antacids or aluminum excess in the dialysis regimen (Chap. 429).


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InternalMed_Harrison. Milk-Alkali Syndrome The milk-alkali syndrome is due to excessive ingestion of calcium and absorbable antacids such as milk or calcium carbonate. It is much less frequent since proton pump inhibitors and other treatments became available for peptic ulcer disease. For a time, the increased use of calcium carbonate in the management of secondary hyperparathyroidism led to reappearance of the syndrome. Several clinical presentations—acute, subacute, and chronic—have 2479 been described, all of which feature hypercalcemia, alkalosis, and renal failure. The chronic form of the disease, termed Burnett’s syndrome, is associated with irreversible renal damage. The acute syndromes reverse if the excess calcium and absorbable alkali are stopped.


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InternalMed_Harrison. Individual susceptibility is important in the pathogenesis, because some patients are treated with calcium carbonate and alkali regimens without developing the syndrome. One variable is the fractional calcium absorption as a function of calcium intake. Some individuals absorb a high fraction of calcium, even with intakes ≥2 g of elemental calcium per day, instead of reducing calcium absorption with high intake, as occurs in most normal individuals. Resultant mild hypercalcemia after meals in such patients is postulated to contribute to the generation of alkalosis. Development of hypercalcemia causes increased sodium excretion and some depletion of total-body water. These phenomena and perhaps some suppression of endogenous PTH secretion due to mild hypercalcemia lead to increased bicarbonate resorption and to alkalosis in the face of continued calcium carbonate ingestion. Alkalosis per se selectively enhances calcium resorption in the distal nephron, thus aggravating the


InternalMed_Harrison

InternalMed_Harrison. bicarbonate resorption and to alkalosis in the face of continued calcium carbonate ingestion. Alkalosis per se selectively enhances calcium resorption in the distal nephron, thus aggravating the hypercalcemia. The cycle of mild hypercalcemia → bicarbonate retention → alkalosis → renal calcium retention → severe hypercalcemia perpetuates and aggravates hypercalcemia and alkalosis as long as calcium and absorbable alkali are ingested.


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InternalMed_Harrison. DIFFERENTIAL DIAGNOSIS: SPECIAL TESTS Differential diagnosis of hypercalcemia is best achieved by using clini cal criteria, but immunometric assays to measure PTH are especially useful in distinguishing among major causes (Fig. 424-6). The clinical features that deserve emphasis are the presence or absence of symptoms or signs of disease and evidence of chronicity. If one discounts fatigue or depression, >90% of patients with primary hyperparathyroidism have asymptomatic hypercalcemia; symptoms of malignancy are usually present in cancer-associated hypercalcemia. Disorders other than hyperparathyroidism and malignancy cause <10% of cases of hypercalcemia, and some of the nonparathyroid causes are associated with clear-cut manifestations such as renal failure.


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InternalMed_Harrison. Hyperparathyroidism is the likely diagnosis in patients with chronic hypercalcemia. If hypercalcemia has been manifest for >1 year, malignancy can usually be excluded as the cause. A striking feature of malignancy-associated hypercalcemia is the rapidity of the course, (lithium, thiazides) Immobilization FIGURE 424-6 Algorithm for the evaluation of patients with hypercalcemia. See text for details. FHH, familial hypocalciuric hypercalcemia; MEN, multiple endocrine neoplasia; PTH, parathyroid hormone; PTHrP, parathyroid hormone–related peptide.


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InternalMed_Harrison. 2480 whereby signs and symptoms of the underlying malignancy are evident within months of the detection of hypercalcemia. Although clinical considerations are helpful in arriving at the correct diagnosis of the cause of hypercalcemia, appropriate laboratory testing is essential for definitive diagnosis. The immunoassay for PTH usually separates hyperparathyroidism from all other causes of hypercalcemia (exceptions are very rare reports of ectopic production of excess PTH by nonparathyroid tumors). Patients with hyperparathyroidism have elevated PTH levels despite hypercalcemia, whereas patients with malignancy and the other causes of hypercalcemia (except for disorders mediated by PTH such as lithium-induced hypercalcemia) have levels of hormone below normal or undetectable levels. Assays based on the double-antibody method for PTH exhibit very high sensitivity (especially if serum calcium is simultaneously evaluated) and specificity for the diagnosis of primary hyperparathyroidism


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InternalMed_Harrison. based on the double-antibody method for PTH exhibit very high sensitivity (especially if serum calcium is simultaneously evaluated) and specificity for the diagnosis of primary hyperparathyroidism (Fig. 424-4). In summary, PTH values are elevated in >90% of parathyroid-related causes of hypercalcemia, undetectable or low in malignancy-related hypercalcemia, and undetectable or normal in vitamin D– related and high-bone-turnover causes of hypercalcemia. In view of the specificity of the PTH immunoassay and the high frequency of hyperparathyroidism in hypercalcemic patients, it is cost-effective to measure the PTH level in all hypercalcemic patients unless malignancy or a specific nonparathyroid disease is obvious. False-positive PTH assay results are rare. Immunoassays for PTHrP are helpful in diagnosing certain types of malignancy-associated hypercalcemia. Although FHH is parathyroid-related, the disease should be managed distinctively from hyperparathyroidism. Clinical features and


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InternalMed_Harrison. in diagnosing certain types of malignancy-associated hypercalcemia. Although FHH is parathyroid-related, the disease should be managed distinctively from hyperparathyroidism. Clinical features and the low urinary calcium excretion can help make the distinction. Because the incidence of malignancy and hyperparathyroidism both increase with age, they can coexist as two independent causes of hypercalcemia. 1,25(OH)2D levels are elevated in many (but not all) patients with primary hyperparathyroidism. In other disorders associated with hypercalcemia, concentrations of 1,25(OH)2D are low or, at the most, normal. However, this test is of low specificity and is not cost-effective, as not all patients with hyperparathyroidism have elevated 1,25(OH)2D levels and not all nonparathyroid hypercalcemic patients have suppressed 1,25(OH)2D. Measurement of 1,25(OH)2D is, however, critically valuable in establishing the cause of hypercalcemia in sarcoidosis and certain lymphomas. A useful general


InternalMed_Harrison

InternalMed_Harrison. patients have suppressed 1,25(OH)2D. Measurement of 1,25(OH)2D is, however, critically valuable in establishing the cause of hypercalcemia in sarcoidosis and certain lymphomas. A useful general approach is outlined in Fig. 424-6. If the patient is asymptomatic and there is evidence of chronicity to the hypercalcemia, hyperparathyroidism is almost certainly the cause. If PTH levels (usually measured at least twice) are elevated, the clinical impression is confirmed and little additional evaluation is necessary. If there is only a short history or no data as to the duration of the hypercalcemia, occult malignancy must be considered; if the PTH levels are not elevated, then a thorough workup must be undertaken for malignancy, including chest x-ray, CT of chest and abdomen, and bone scan. Immunoassays for PTHrP may be especially useful in such situations. Attention should also be paid to clues for underlying hematologic disorders such as anemia, increased plasma globulin, and abnormal


InternalMed_Harrison

InternalMed_Harrison. Immunoassays for PTHrP may be especially useful in such situations. Attention should also be paid to clues for underlying hematologic disorders such as anemia, increased plasma globulin, and abnormal serum immunoelectrophoresis; bone scans can be negative in some patients with metastases such as in multiple myeloma. Finally, if a patient with chronic hypercalcemia is asymptomatic and malignancy therefore seems unlikely on clinical grounds, but PTH values are not elevated, it is useful to search for other chronic causes of hypercalcemia such as occult sarcoidosis. A careful history of dietary supplements and drug use may suggest intoxication with vitamin D or vitamin A or the use of thiazides.


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InternalMed_Harrison. The approach to medical treatment of hypercalcemia varies with its severity (Table 424-4). Mild hypercalcemia, <3 mmol/L (12 mg/ dL), can be managed by hydration. More severe hypercalcemia (levels of 3.2–3.7 mmol/L [13–15 mg/dL]) must be managed aggressively; above that level, hypercalcemia can be life-threatening and requires emergency measures. By using a combination of approaches in severe hypercalcemia, the serum calcium concentration can be decreased by 0.7–2.2 mmol/L (3–9 mg/dL) within 24–48 h in most patients, enough to relieve acute symptoms, prevent death from hypercalcemic crisis, and permit diagnostic evaluation. Therapy can then be directed at the underlying disorder—the second priority.


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InternalMed_Harrison. Hypercalcemia develops because of excessive skeletal calcium release, increased intestinal calcium absorption, or inadequate renal calcium excretion. Understanding the particular pathogenesis helps guide therapy. For example, hypercalcemia in patients with malignancy is primarily due to excessive skeletal calcium release and is, therefore, minimally improved by restriction of dietary calcium. On the other hand, patients with vitamin D hypersensitivity or vitamin D intoxication have excessive intestinal calcium absorption, and restriction of dietary calcium is beneficial. Decreased renal function or ECF depletion decreases urinary calcium excretion. In such situations, rehydration may rapidly reduce or reverse the hypercalcemia, even though increased bone resorption persists. As outlined below, the more severe the hypercalcemia, the greater the number of combined therapies that should be used. Rapid-acting (hours) approaches—rehydration, forced diuresis, and calcitonin—can be used with


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InternalMed_Harrison. the more severe the hypercalcemia, the greater the number of combined therapies that should be used. Rapid-acting (hours) approaches—rehydration, forced diuresis, and calcitonin—can be used with the most effective antiresorptive agents such as bisphosphonates (since severe hypercalcemia usually involves excessive bone resorption).


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InternalMed_Harrison. HYDRATION, INCREASED SALT INTAKE, MILD AND FORCED DIURESIS


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InternalMed_Harrison. The first principle of treatment is to restore normal hydration. Many hypercalcemic patients are dehydrated because of vomiting, inanition, and/or hypercalcemia-induced defects in urinary concentrating ability. The resultant drop in glomerular filtration rate is accompanied by an additional decrease in renal tubular sodium and calcium clearance. Restoring a normal ECF volume corrects these abnormalities and increases urine calcium excretion by 2.5–7.5 mmol/d (100–300 mg/d). Increasing urinary sodium excretion to 400–500 mmol/d increases urinary calcium excretion even further than simple rehydration. After rehydration has been achieved, saline can be administered, or furosemide or ethacrynic acid can be given twice daily to depress the tubular reabsorptive mechanism for calcium (care must be taken to prevent dehydration). The combined use of these therapies can increase urinary calcium excretion to ≥12.5 mmol/d (500 mg/d) in most hypercalcemic patients. Because this is a substantial


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InternalMed_Harrison. be taken to prevent dehydration). The combined use of these therapies can increase urinary calcium excretion to ≥12.5 mmol/d (500 mg/d) in most hypercalcemic patients. Because this is a substantial percentage of the exchangeable calcium pool, the serum calcium concentration usually falls 0.25–0.75 mmol/L (1–3 mg/dL) within 24 h. Precautions should be taken to prevent potassium and magnesium depletion; calcium-containing renal calculi are a potential complication.


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InternalMed_Harrison. Under life-threatening circumstances, the preceding approach can be pursued more aggressively, but the availability of effective agents to block bone resorption (such as bisphosphonates) has reduced the need for extreme diuresis regimens (Table 424-4). Depletion of potassium and magnesium is inevitable unless replacements are given; pulmonary edema can be precipitated. The potential complications can be reduced by careful monitoring of central venous pressure and plasma or urine electrolytes; catheterization of the bladder may be necessary. Dialysis treatment may be needed when renal function is compromised.


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InternalMed_Harrison. The bisphosphonates are analogues of pyrophosphate, with high affinity for bone, especially in areas of increased bone turnover, where they are powerful inhibitors of bone resorption. These bone-seeking compounds are stable in vivo because phosphatase enzymes cannot hydrolyze the central carbon-phosphorus-carbon bond. The bisphosphonates are concentrated in areas of high bone turnover and are taken up by and inhibit osteoclast action; the mechanism of action is complex. The bisphosphonate molecules that contain amino groups in the side chain structure (see below) interfere with prenylation of proteins and can lead to cellular apoptosis. The highly active nonamino group–containing bisphosphonates are also metabolized to cytotoxic products.


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InternalMed_Harrison. The initial bisphosphonate widely used in clinical practice, etidronate, was effective but had several disadvantages, including the capacity to inhibit bone formation as well as blocking resorption. Subsequently, a number of secondor third-generation compounds have become the mainstays of antiresorptive therapy for treatment of hypercalcemia and osteoporosis. The newer bisphosphonates have a highly favorable ratio of blocking resorption versus inhibiting bone formation; they inhibit osteoclast-mediated skeletal resorption yet do not cause mineralization defects at ordinary doses. Although the bisphosphonates have similar structures, the routes of administration, efficacy, toxicity, and side effects vary. The potency of the compounds for inhibition of bone resorption varies more than 10,000-fold, increasing in the order of etidronate, tiludronate, pamidronate, alen-2481 dronate, risedronate, and zoledronate. The IV use of pamidronate and zoledronate is approved for the treatment of


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InternalMed_Harrison. increasing in the order of etidronate, tiludronate, pamidronate, alen-2481 dronate, risedronate, and zoledronate. The IV use of pamidronate and zoledronate is approved for the treatment of hypercalcemia; between 30 and 90 mg pamidronate, given as a single IV dose over a few hours, returns serum calcium to normal within 24–48 h with an effect that lasts for weeks in 80–100% of patients. Zoledronate given in doses of 4 or 8 mg/5-min infusion has a more rapid and more sustained effect than pamidronate in direct comparison.


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InternalMed_Harrison. These drugs are used extensively in cancer patients. Absolute survival improvements are noted with pamidronate and zoledronate in multiple myeloma, for example. However, although still rare, there are increasing reports of jaw necrosis, especially after dental surgery, mainly in cancer patients treated with multiple doses of the more potent bisphosphonates.


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InternalMed_Harrison. Calcitonin acts within a few hours of its administration, principally through receptors on osteoclasts, to block bone resorption. Calcitonin, after 24 h of use, is no longer effective in lowering calcium. Tachyphylaxis, a known phenomenon with this drug, seems to explain the results, since the drug is often effective in the first 24 h of use. Therefore, in life-threatening hypercalcemia, calcitonin can be used effectively within the first 24 h in combination with rehydration and saline diuresis while waiting for more sustained effects from a simultaneously administered bisphosphonate such as pamidronate. Usual doses of calcitonin are 2–8 U/kg of body weight IV, SC, or IM every 6–12 h.


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InternalMed_Harrison. IV, SC, or IM every 6–12 h. Denosumab, an antibody that blocks the RANK ligand (RANKL) and dramatically reduces osteoclast number and function, is approved for therapy of osteoporosis. It also appears to be an effective treatment to reverse hypercalcemia of malignancy, but is not yet approved for this indication. Plicamycin (formerly mithramycin), which inhibits bone resorption, and gallium nitrate, which exerts a hypocalcemic action also by inhibiting bone resorption, are no longer used because of superior alternatives such as bisphosphonates.


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InternalMed_Harrison. Glucocorticoids have utility, especially in hypercalcemia complicating certain malignancies. They increase urinary calcium excretion and decrease intestinal calcium absorption when given in pharmacologic doses, but they also cause negative skeletal calcium balance. In normal individuals and in patients with primary hyperparathyroidism, glucocorticoids neither increase nor decrease the serum calcium concentration. In patients with hypercalcemia due to certain osteolytic malignancies, however, glucocorticoids may be effective as a result of antitumor effects. The malignancies in which hypercalcemia responds to glucocorticoids include multiple myeloma, leukemia, Hodgkin’s disease, other lymphomas, and carcinoma of the breast, at least early in the course of the disease. Glucocorticoids are also effective in treating hypercalcemia due to vitamin D intoxication and sarcoidosis. Glucocorticoids are also useful in the rare form of hypercalcemia, now recognized in certain autoimmune disorders


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InternalMed_Harrison. effective in treating hypercalcemia due to vitamin D intoxication and sarcoidosis. Glucocorticoids are also useful in the rare form of hypercalcemia, now recognized in certain autoimmune disorders in which inactivating antibodies against the receptor imitate FHH. Elevated PTH and calcium levels are effectively lowered by the glucocorticoids. In all the preceding situations, the hypocalcemic effect develops over several days, and the usual glucocorticoid dosage is 40–100 mg prednisone (or its equivalent) daily in four divided doses. The side effects of chronic glucocorticoid therapy may be acceptable in some circumstances.


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InternalMed_Harrison. Dialysis is often the treatment of choice for severe hypercalcemia complicated by renal failure, which is difficult to manage medically. Peritoneal dialysis with calcium-free dialysis fluid can remove 5–12.5 mmol (200–500 mg) of calcium in 24–48 h and lower the serum calcium concentration by 0.7–3 mmol/L (3–12 mg/dL). Large quantities of phosphate are lost during dialysis, and serum inorganic phosphate concentration usually falls, potentially aggravating hypercalcemia. Therefore, the serum inorganic phosphate concentration


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InternalMed_Harrison. Disorders of the Parathyroid Gland and Calcium Homeostasis 2482 should be measured after dialysis, and phosphate supplements should be added to the diet or to dialysis fluids if necessary. Phosphate therapy, PO or IV, has a limited role in certain circumstances (Chap. 423). Correcting hypophosphatemia lowers the serum calcium concentration by several mechanisms, including bone/calcium exchange. The usual oral treatment is 1–1.5 g of phosphorus per day for several days, given in divided doses. It is generally believed, but not established, that toxicity does not occur if therapy is limited to restoring serum inorganic phosphate concentrations to normal. Raising the serum inorganic phosphate concentration above normal decreases serum calcium levels, sometimes strikingly. Intravenous phosphate is one of the most dramatically effective treatments available for severe hypercalcemia but is toxic and even dangerous (fatal hypocalcemia). For these reasons, it is used rarely and only in


InternalMed_Harrison

InternalMed_Harrison. is one of the most dramatically effective treatments available for severe hypercalcemia but is toxic and even dangerous (fatal hypocalcemia). For these reasons, it is used rarely and only in severely hypercalcemic patients with cardiac or renal failure where dialysis, the preferable alternative, is not feasible or is unavailable.