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Irvin III GL, Carneiro DM. Management Changes in Primary Hyperparathyroidism. JAMA. 2000;284(8):934–936. doi:10.1001/jama.284.8.934
Author Affiliations: Department of Surgery, Jackson Memorial Hospital, University of Miami and Department of Veterans Affairs Medical Center, Miami, Fla.
Contempo Updates Section Editor: Stephen
J. Lurie, MD, PhD, Contributing Editor.
With few exceptions, patients with hypercalcemia, normal renal function,
and an elevated intact parathyroid hormone level have primary hyperparathyroidism.
Currently, definitive treatment of this disease involves parathyroidectomy,
which is the surgical removal of hypersecreting parathyroid gland(s), a procedure
that involves surgical exploration of the neck, usually under general anesthesia.
Patients with overt symptoms associated with this disease (eg, urinary tract
stones, bone pain, cognitive symptoms) and marked hypercalcemia (calcium level
>1.0 mg/dL [0.25 mmol/L] above normal range) are usually referred for parathyroidectomy.
This procedure results in normocalcemia in 95% to 98% of patients and symptomatic
improvement in 82%.1-3
A more difficult management dilemma occurs in the 80% of patients with hyperparathyroidism
presenting with mild hypercalcemia and minimal or no symptoms.
In the last 10 years, several technological advances have influenced
the diagnosis and treatment of patients with primary hyperparathyroidism.
Perhaps the most important of these has been the widespread availability of
laboratory assays for measuring intact parathyroid hormone (1-84). First described
in 1987,4 this 2-site antibody assay has proven
to be much more sensitive than previous assays, which measured only parts
of the parathyroid hormone molecule. This specific assay has allowed more
precise diagnosis of primary hyperparathyroidism in patients presenting with
hypercalcemia. The management of less common etiologies, such as familial,
secondary, or tertiary hyperparathyroidism, and multiple endocrine neoplasia,
however, remains more complex and will not be discussed in this article.
Historically, the standard surgical approach in patients with primary
hyperparathyroidism has consisted of general endotracheal anesthesia followed
by bilateral neck exploration. Surgeons typically visualize all 4 glands and
excise the grossly enlarged parathyroid glands, while leaving sufficient parathyroid
tissue for normal function. At the time of surgery, however, it can be difficult
to determine whether all the hypersecreting tissue has been removed. Some
surgeons have used gland excision based on biopsy of parathyroid tissue with
frozen section histopathology, but its diagnostic accuracy in determining
adenoma vs hyperplasia is inconsistent and has not proven helpful in the operative
decision of single or multiple gland involvement. Thus, the success of this
operative approach historically has depended largely on the experience and
judgment of the surgeon. Due to individual preference or insurance constraints,
many patients undergo parathyroidectomy in hospitals where this procedure
is only performed occasionally and the surgeon has limited experience. Failure
to achieve postoperative normocalcemia occurred in 30% of patients in Scandinavian
hospitals in which fewer than 10 parathyroidectomies were performed per year.5 Comparable studies have not been published in United
States, but these findings have stimulated the development of several new
surgical adjuncts to improve success rates and decrease operative morbidity.
Preoperative localization of the hypersecreting parathyroid gland(s)
has been attempted by many techniques. The most sensitive appear to be ultrasonography
(which is operator-dependent) and technetium-99-m sestamibi tomographic reprojection
nuclear scanning (DuPont Merck Pharmaceutical, Billerica, Mass). The advantage
of the computerized nuclear scan is the ability to print a 3-dimensional image,
which can be taken to the operating room for visual reference by the surgeon.
This radioisotope, which demonstrates good affinity for hypersecreting parathyroid
glands, has led some surgeons to use a radio-guided probe to assist in finding
the abnormal tissue.6 This method has some
distinct advantages, but many surgeons find that a probe is not helpful or
needed when the sestamibi scan clearly identifies the anatomical location
of an overactive gland. With a sensitivity of 69% and specificity of 98%,7 the data from the sestamibi scan alone are limited
in guiding the extent of resection. It can, however, direct the dissection
to sites suspected of harboring hyperfunctioning glands.
Another innovative surgical adjunct in parathyroidectomy is the use
of intraoperative, rapid parathyroid hormone assay. Because the half-life
of parathyroid hormone is 3 to 4 minutes, successful excision of all hyperfunctioning
parathyroid tissue can be rapidly confirmed in the operating room. This method,
which has been commercially available since 1996 (Nichols Institute Diagnostics,
San Juan Capistrano, Calif), provides a 10-minute assay of the plasma parathyroid
hormone level that can be used during parathyroidectomy to determine quantitatively
when all hyperfunctioning parathyroid tissue has been excised. Specifically,
a decrease of 50% from the preoperative or preexcision parathyroid hormone
level in peripheral blood plasma measured 10 minutes after gland excision
predicts a postoperative return to normal or low serum calcium levels with
an overall accuracy of 97%.8 On the other hand,
an insufficient decrease in the hormone level after excision of a suspected
parathyroid gland signals that more hypersecreting tissue is present, thus
leading the surgeon to further exploration until all hyperfunctioning parathyroid
tissue is excised.
Multiglandular disease, as identified by this quantitative biochemical
frozen section, is present in 5% of patients with primary hyperparathyroidism
and must be recognized and treated at the time of operation to ensure operative
success.9 In contrast, a 14% to 24% incidence
rate of multiglandular disease has been reported previously in patients with
sporadic primary hyperparathyroidism when resection is based on a surgeon's
judgment of gland size during traditional bilateral neck exploration.10-12
Intraoperative measurement of parathyroid hormone can also help the
surgeon find and excise obscure or previously overlooked glands. The rapid
parathyroid hormone assay is useful in patients with inaccurate or negative
scans. For these difficult-to-find glands, rapid parathyroid hormone assay
can be extremely beneficial by facilitating their localization with differential
venous sampling, measuring the increase in hormone secretion after massage
of specific areas, and correctly identifying the excision of abnormal parathyroid
tissue when it is not easily recognized.13
With this operative approach, frozen section histopathology is rarely
needed, operating time is shortened, and with a limited dissection, the patient
can safely go home 2 to 3 hours after surgery. A serum calcium level can be
obtained the next day in an outpatient setting and, in case of advanced osteoporosis,
anticipated hypocalcemia can be treated prophylactically with oral calcium
supplementation. This combination of surgical adjunctive techniques offers
a real advance in the surgical approach to hyperparathyroidism.
Several recent reports indicate that these new techniques can not only
improve the success rate of parathyroidectomy as measured by a return to normocalcemia
in 98% of patients,8 but it can also substantially
simplify the operation, from a bilateral neck exploration under general anesthesia
with the accompanying morbidity, to a simpler outpatient procedure.14 Most patients would be eligible for parathyroidectomy
(under local anesthesia) through a small (3-cm) incision, with limited, target-specific
dissection. Excision of the hyperfunctioning gland(s) could be confirmed in
the operating room by a quantitative decrease in the plasma parathyroid hormone
level, which would assure the surgeon that all hypersecreting tissue has been
removed, without the need for further dissection or visualization of the remaining
glands. The failure rate of this minimally invasive procedure is 1.3% to 1.5%.15,16 Furthermore, surgeons who are qualified
to perform a bilateral neck exploration for primary hyperparathyroidism should
be capable of performing a minimally invasive procedure if the described surgical
adjuncts are available. Any hospital can have these commercially available
adjuncts and the costs appear to vary with surgical volume.14,17
In 1990, the National Institutes of Health Consensus provided guidelines
for the management and treatment of patients with primary hyperparathyroidism.
These guidelines recommended parathyroidectomy for patients with symptoms,
marked hypercalcemia of 1.0-1.6 mg/dL (0.25-0.40 mmol/L) above normal range,
urinary stones, urinary calcium excretion of more than 400 mg/24 h (10 mmol/d),
bone mass of 2 SDs or more below those of persons matched by age, sex, and
race (z score), age younger than 50 years, and decreasing
renal function.18 Because cases today are frequently
diagnosed at a much milder or earlier stage of this disease, the decision
of nonoperative observation vs parathyroidectomy has become more complex.
Many patients tolerate mild hyperparathyroidism well without operative treatment.
A recent study has shown that 73% of asymptomatic patients presenting with
mild hypercalcemia (10.3-10.5 mg/dL [2.47-2.63 mmol/L]) did well over a 10-year
period, without loss of cortical bone, progressive hypercalcemia, or excessive
urinary calcium excretion. On the other hand, 27% of patients in this study
had progressive disease, which led to parathyroidectomy.19
Unfortunately, there are currently no factors that can predict which patients
will experience progressive disease.
Patients with osteoporosis will have a prompt and sustained increase
in their bone mineral density (BMD) after successful parathyroidectomy. Although
there are no studies relating the incidence of fractures to hyperparathyroidism,
there was an average 6% increase in BMD of the femoral neck 1 year after parathyroidectomy,
and 14% after 10 years.19 In patients with
osteoporosis associated with hyperparathyroidism, this improvement is a well-defined
benefit of parathyroidectomy. It should be pointed out, however, that patients
with primary hyperparathyroidism have a higher incidence of cortical than
trabecular bone loss. Because of its high cortical bone composition, the distal
one third of the radius should be studied with BMD in these patients. This
site is more specific for evaluation of bone loss caused by hyperparathyroidism
than the lumbar spine or hip, since these are also affected by other causes
of bone loss such as age and estrogen deficiency.
How do these new findings influence the management of patients with
primary hyperparathyroidism? With less traumatic, limited parathyroidectomy
available, the benefit of surgical treatment with minimal risks needs to be
reevaluated. For instance, symptomatic elderly patients with comorbid disease,
who are frequently denied operation due to risks related to anesthesia and
bilateral neck dissection, might now be candidates for safe, minimally invasive
parathyroidectomy resulting in marked relief of symptoms. On the other hand,
we suggest that patients with mild hypercalcemic hyperparathyroidism (<0.4
mg/dL [0.1 mmol/L] above range) be followed up for 1 year to confirm the diagnosis
in that some will return to normocalcemia20
and 73% will show no progressive disease.19
Parathyroidectomy is indicated in patients with progressive disease as described
in Table 1.
In centers in which limited parathyroidectomy is available, asymptomatic
patients with moderate hypercalcemia (0.4-0.9 mg/dL [0.1-0.23 mmol/L] above
normal range) can be considered for earlier parathyroidectomy before severe
bone loss or kidney damage occurs. We recommend consideration for parathyroidectomy
if the BMD z score is lower than −1.0 in the
forearm, or if urinary calcium excretion is greater than 300 mg/24 h (7.5
mmol/d). If only minimal bone density loss and normal urinary calcium excretion
is shown by these quantitative tests, serial examinations are indicated to
diagnose progressive disease. Hypercalcemia at the level of 1.0 mg/dL (0.25
mmol/L) or more above normal range should itself be considered an indication
Based on the current data referenced in this review, we suggest a management
scheme for patients with primary hyperparathyroidism as shown in Table 1. With a highly successful and less
traumatic parathyroidectomy available today, our present guidelines differ
from the National Institutes of Health Consensus report.18
We suggest operative treatment in patients with less bone loss in the forearm,
mild elevation of urinary calcium excretion, and in asymptomatic patients
older than 50 years to prevent continuing bone loss and/or renal involvement.
Armed with a secure diagnosis, good quantitative measurements of BMD,
and a more thorough understanding of the clinical course of patients with
mild hyperparathyroidism, the therapeutic options are more clearly defined.
By monitoring these patients to detect stable or progressive disease and providing
better results using a minimally invasive outpatient parathyroidectomy, real
progress in the management of patients with primary hyperparathyroidism can
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