13 Jan
Because of its hereditary nature, the clinical appearance of hy- perparathyroidism in MEN 2A is rather early in risk subjects, around 35 years old, compared to the average 50 years old of the sporadic form; the onset age in the MEN 1 form is around 25-30 years old.
Often, an “incidental” parathyroid tumor is detected during thyroid removal for MTC.
From a clinical point of view, it is characterized by mild hyper- calcaemia, that is mainly asymptomatic: only 15-25% of the subjects can be found with symptoms such as kidney stones or osteoporosis. In sporadic disease, the symptomatic forms account for 5-10% of the cases, while in MEN 1 patients the percentage rises above 50%. In a multicentric European retrospective study, in a sample of 67 subjects affected with PHPT MEN 2A related, 84% of the cases were found with asymptomatic hyperparathyroidism, while the remaining 16% were symptomatic (10 patients had kidney stones and one patient had bone disease). Serum calcium was slightly higher in 69% of the subjects (less than 3 mmol l-1), while in the normal range for 16% of them. Also, both MTC and hyperparathyroidism were diagnosed at the time of exploratory neck surgery in 75% of the sample, while for 4% and 18% the diagnosis of PHPT was available before or after surgery, respectively. Of note, patients in whom PHPT and MTC were diagnosed synchronously often had normal serum levels of calcium and parathyroid hormone (PTH) and the diagnosis of PHPT was based on morphology (enlargement of one or more glands) or histology. Thus, beyond the biological behaviour of parathyroid tumors, the earlier onset of MTC leading to an early diagnosis of PHPT and/or a strict clinical monitoring for the development of parathyroid disease might justify the large number of asymptomatic patients.
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12 Jan
A germ-line RET point mutation has been described in over 92% of MEN 2 families. Therefore, DNA testing for RET mutations has been proposed as a confirmative test in patients with a clinical suspicion of MEN 2 syndrome and as a predictive test in asymptomatic patients who are clinically at risk. The high sensitivity and specificity of the molecular test and its considerable impact in diagnosis and therapy have led to the introduction of RET testing in routine clinical practice.
By pooling a considerable amount of MEN 2 family data, a close relationship between genotype and phenotype has been described. MEN 2A has been associated with mutations in exon 10 (codons 609, 611, 618 and 620), exon 11 (codons 634, 635, 637), exon 13 (codons 790, 791), exon 14 (V804L) and exon 15 (codon 891); mutations at codon 634 are the most common in MEN 2A, accounting for 85% of cases.
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11 Jan
Introduction
Primary hyperparathyroidism (PHPT) in its hereditary variants represents only about 5% of all PHPT but it assumes several forms, has characteristic associations, and requires special management.
Among all syndromes of hereditary PHPT (multiple endocrine neoplasia type 1 and type 2A, familial hypocalciuric hypercalcemia, neonatal severe PHPT, hyperparathyroidism-jaw tumor syndrome, and familial isolated hyperparathyroidism) (Table I), MEN 2A is the only one in which PHPT is not the most common endocrine feature because it occurs in approximately 19% to 35% of affected family members (Table II). In fact, more frequently clinical features of the MEN 2A syndrome include medullary thyroid carcinoma (MTC) and/or C-cell hyperplasia in almost all affected individuals, and pheochromocy- toma in over 50% of patients. Therefore, it has been difficult to study the natural history of PHPT in MEN 2 because of its low incidence and the frequent late onset of clinical manifestations of hyperparathyroidism. Moreover, parathyroid disease is rarely the first feature recognized in MEN 2A, is generally mild and is sometimes expressed only as parathyroid tumors discovered incidentally in MTC surgery. Primary hyperparathyroidism in MEN 2A is a disease which is different from those observed in other hereditary neoplastic variants (i.e., MEN 1 and hyperparathyroidism-jaw tumor syndrome). In fact, the high rate of cure achieved with well-performed parathyroid surgery, as well as the low rate of persistence or recurrence of the disease, demonstrate that MEN 2A-related PHPT is a much less aggressive condition than is usually suggested.
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10 Jan
Calcimimetics. A more targeted approach to the medical therapy of primary hyperparathyroidism is to interfere specifically with the production of PTH. A new class of agents that alters the function of the extracellular calcium-sensing receptor offers an exciting new approach to primary hyperparathyroidism. By binding to an allosteric site, these agents increase the affinity of extracellular calcium for the calcium receptor, leading to reduction in PTH secretion. Such agents, therefore, could conceivably be utilized to reduce PTH and serum calcium levels in hyperparathyroid states. An early clinical experience with postmenopausal women who had mild primary hyperparathyroidism showed that, in principle, a calcimimetic can significantly reduce PTH and serum calcium levels in this disease. More recent experience has been gained with a newer calcimimetic, cinacalcet. This agent has been studied in the hy- perparathyroidism associated with renal failure, in primary hyperparathyroidism and in parathyroid cancer. So far, cinacalcet has been approved by the FDA only for the management of patients in renal failure on dialysis with secondary hyperparathyroidism and in patients with parathyroid carcinoma. Even though the drug has not been approved yet for primary hyperparathyroidism, the early data are promising. Shoback et al. studied 22 patients with primary hyper- parathyroidism. In this dose-ranging study, patients were given placebo or drug in amounts of 30, 40, or 50 mg twice daily for 15 days. In all dose groups, except placebo, cinacalcet was associated with a normalization of the serum calcium after the second dose and remained within normal limits for the entire two-week period. Maximal reductions in PTH, over 50 percent, occurred two to four hours after dosing in all cinacalcet-treated groups. This reduction occurred when tested at both day one and day two of the study. There were no significant changes in urinary calcium excretion. Both serum calcium and PTH returned toward baseline by seven days after cinacalcet was stopped. Peacock et al. have recently reported their experience in a longer study of cinacalcet. This multicenter, randomized, double-blind, placebo-controlled trial was designed to evaluated the longer term actions of cinacalcet in 78 patients with primary hyperparathyroidism. Cinacalcet was titrated from 30-50 mg twice daily during a 12-week period followed by a 12- week maintenance and 28-week follow-up period. Most patients treated with cinacalcet achieved the primary endpoint, namely normocalcemia (Fig. 3). Normal calcium concentrations were maintained for the entire duration of the study. Modest, but significant, reductions in the plasma PTH concentration were observed in the cinacalcet group. Similar to the study of Shoback, PTH levels fell quickly within hours after the administration of drug. This experience has been extended to three years over which time the majority patients with primary hyperparathyroidism who were treated with cinacalcet demonstrated excellent maintenance of a normal serum serum calcium concentration.
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09 Jan
Pharmacological approaches. At the time of the 2002 Workshop, it was concluded that there were no specific medical or pharmacological therapies for which there was yet convincing evidence of efficacy and/or safety. Since that time, experience has accumulated with several of these therapies. These include the report from the Women’s Health Initiative that emphasizes increased risks for long-term estrogen alone or with progestin. Even without this evidence, there was little clear rationale for long-term estrogen use despite its documented ability at higher doses (1.25 mg or occasionally more) to lower calcium to normal without increasing PTH levels. Side-effect profile and the newer data about risk would seem to limit its applicability. Experience has suggested, however, that selective estrogen receptor modulators, bisphosphonates and calcimimetics do have promise as specific pharmacological treatments. In certain patients, such pharmacological approaches to the management of hyperparathyroidism are particularly desirable, such as those who meet guidelines for parathyroid surgery but refuse surgery or have medical contraindications. For those who do not meet surgical guidelines, approaches that safely lower serum calcium or increase bone density are attractive. These pharmacological approaches to control hypercalcemia are also useful in patients with parathyroid carcinoma when repeated attempts to resect malignant tissue have ultimately failed. In this section, we describe cumulative experience with pharmacological approaches.
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08 Jan
If the guidelines offered by the expert panel convened after the Workshop on Aymptomatic Primary Hyperparathyroidism are followed, about 40-50 percent of patients with primary hy- perparathyroidism in the United States will fit into the non-surgical, conservative management category. The natural history of this cohort indicates that over a 10-year period, patients in general are remarkably stable. The group data show that serum and urine biochemical parameters are stable. Similarly, in the majority of patients, bone mineral density is unchanged at lumbar spine, hip and distal radius after 10 years. When these data for the group as a whole are reviewed more closely, however, it is clear that some patients who are followed without surgery will show changes and thus meet criteria for surgery. In about 25 percent of these patients followed without surgery over 10 years, guidelines for surgery were met eventually by virtue of an increasing serum or urinary calcium or declining bone mineral density. The fact that an appreciable number of asymptomatic patients will progress to meet criteria for surgery emphasizes the need for all these patients to be monitored.
Monitoring asymptomatic patients who are not to undergo surgery
The Panel of the 2002 Workshop on Asymptomatic Primary Hyperparathyroidism recommended a plan for monitoring patients who are not to undergo parathyroid surgery (Table II). The serum calcium measurement should be made every six months, while it is not considered necessary to monitor the urinary calcium excretion on a regular basis. Renal function can be monitored by the yearly serum creatinine concentration and the Cockcroft-Gault relationship. The panel emphasized the utility of measuring annually bone density at the lumbar spine, hip and distal 1/3 radius site.
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07 Jan
In the hands of an expert parathyroid surgeon, parathyroidec- tomy is a highly successful procedure with infrequent complications. Both the classic approach of neck exploration, usually with efforts to examine all four parathyroid glands and the increasingly popular minimimally invasive parathyroidectomy that uses local rather than general anesthesia are associated with cure in over 95 percent of cases.
The minimally invasive procedure requires successful preoperative localization of the abnormal parathyroid gland and capability to measure PTH rapidly in the operating room. Preoperative blood is obtained for comparison of the PTH concentration with an intraoperative sample obtained minutes after removal of the “abnormal” parathyroid gland. If the level falls by more than 50 percent immediately following resection, the gland that has been removed is considered to be the sole source of overactive parathyroid tissue and the operation is terminated. If the PTH level does not fall by more than 50 percent, the operation is extended to a more traditional one in a search for other overactive parathyroid tissue. There is a risk (albeit small) that the minimally invasive procedure may miss other overactive gland(s) that are less active in the presence of a dominant gland. With advances in imaging technology and growing experience with minimally invasive parathyroid surgery, it is likely that these newer approaches will become more widely used.
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