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Clinical update: sporadic primary hyperparathyroidism


Primary hyperparathyroidism is a biochemical syndrome thyroidism of up to 3·4% in menopausal women.2 Chronic
caused by increased secretion of parathyroid hormone hypercalcaemia causes renal lithiasis, nephrocalcinosis,
(PTH) from one or more of the parathyroid glands. calcification of vascular and heart valve-cusps, acute or
About 5% of cases are an autosomal dominant inheri- chronic calcifying pancreatitis, and chondrocalcinosis,
ted disease, mostly caused by multiple adenomas and all of which can occur in primary hyperparathyroidism.
presenting as an isolated condition (familial primary In 5% of cases, the syndrome is diagnosed after acute
hyperparathyroidism) or in the setting of more com- admissions for severe hypercalcaemia (>3·50 mmol/L)
plex syndromes such as multiple endocrine neoplasia with dehydration, renal failure, neurological deterioration
types 1/2 or primary-hyperparathyroidism/jaw-tumour and even coma (parathyrotoxic crisis). Although data on
syndrome. Most cases are sporadic and caused by a the risk of bone fracture are conflicting, recent cohort
single adenoma (85–95%) or multiglandular disease studies suggest that primary hyperparathyroidism is
(5–10%). Less than 1% of cases are caused by a associated with increased risk of vertebral crushing and
parathyroid carcinoma. External radiation and chronic femur, rib, or pelvic fractures, which peaks 5 years before
lithium therapy are the cause of a few sporadic parathyroidectomy.3 Furthermore, non-traditional symp-
parathyroid adenomas. The origin of most benign toms of primary hyperparathyroidism, such as fatigue
parathyroid tumours is unknown. Alterations in or irritability, are more common than in the general
the vitamin D receptor in parathyroid cells are cur- population. The prevalence of arterial hypertension
rently being investigated as a potential cause of cell doubles that of the general population and continues to
proliferation. increase even after parathyroidectomy. The reasons for
Persistently increased serum PTH is associated the association between primary hyperparathyroidism
with activation of PTH and calcitriol receptors in peri- and arterial hypertension remain obscure. Both renal
pheral target organs, the most important of which are impairment and altered intracellular calcium metabolism
the kidney, small intestine, and bone. In the kidney, might be implicated.
PTH activates 1-α-hydroxylase which promotes the The proportion of asymptomatic primary hyper-
synthesis of calcitriol and, in turn, leads to increased parathyroidism is continuously increasing as a result
calcium absorption in the small intestine and to bone of routine calcium measurement. In certain units,
resorption. The biochemical hallmark of primary asymptomatic patients account for more than half
hyperparathyroidism is hypercalcaemia (serum calcium the cases. Some investigators, however, feel that truly
>2·55 mmol/L [10·2 mg/dL, 1 mg/dL=0·25 mmol/L]), asymptomatic primary hyperparathyroidism is not so
which is often associated with hypophosphataemia and common if history taking is accurate enough and if
hypercalciuria of the absorptive type. Diminished bone- target organs and mental status are properly assessed.4
mineral density (osteopenia or osteoporosis) and inc- For example, renal ultrasound can detect asymptomatic
reased markers of bone turnover are also a common renal lithiasis and bone densitometry can show un-
finding. Parathyroid adenoma weight, serum PTH expectedly low bone-mineral density.
concentrations, and the severity of hypercalcaemia are Primary hyperparathyroidism is diagnosed either
related, although less conspicuously so for accompany- because presenting symptoms lead to assay of serum
ing symptoms. If extreme deficiency of vitamin D occurs, calcium, or because hypercalcaemia is detected in
serum calcium may be normal or only moderately patients undergoing a blood test for an apparently
increased, despite very high PTH concentrations and unrelated reason. In settings in which calcium is not
severe bone disease. included in routine blood testing, assay should be
Primary hyperparathyroidism is a common endo- requested in patients with the conditions listed in the
crine disease with an annual incidence of about panel. Primary hyperparathyroidism is the only cause of
20 cases per 100 000.1 Women account for three-quarters hypercalcaemia associated with high concentrations of
of cases that come to surgery, and a screening investi- serum PTH (>55 pg/mL). Hypercalcaemias of tumoral,
gation suggested a prevalence of primary hyperpara- dietary, pharmacological, or endocrine non-parathyroid

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Comment

origin inhibit parathyroid PTH secretion. Tumoral include: calciuria (>10 mmol per 24 h), 30% reduction
hypercalcaemias (pseudohyperparathyroidism) can be in creatinine clearance, osteoporosis (T score less
appropriately diagnosed by measuring the PTH-related than –2·5 at any site), age below 50 years, serum calcium
peptide. Familial hypocalciuric hypercalcaemia is a 1 mg above reference values, and medical surveillance
hereditary disorder, usually asymptomatic, and with impossible or undesirable.6 If no surgical contraindications
mutations of the parathyroid calcium-sensing receptor exist, however, surgery should be discussed with and
gene. It should be considered in the differential diag- offered to almost all patients with asymptomatic primary
nosis of hypercalcaemia, particularly when the calcium hyperparathyroidism because the disease will progress in
urinary excretion is low (<2·5 mmol or 100 mg per 24 h) 30% of cases, long-term medical follow-up is expensive,
or hypercalcaemia persists after an unsuccessful cervical with compliance problems, and there is an increased
exploration. risk of bone fractures and cardiovascular morbidity and
Increased serum PTH is being found in normocalcaemic mortality. On the other hand, surgery cures over 95% of
patients undergoing metabolic bone assessment. These the patients with less than 2% permanent complications
patients probably represent the earliest manifestation and virtually no mortality.
of primary hyperparathyroidism after secondary causes The surgical treatment of primary hyperparathyroid-
of increases in serum PTH have been ruled out.5 ism has undergone a radical change. The increasing
Medical treatment is reserved for patients with use and accuracy of parathyroid scintigraphy and
severe hypercalcaemia or with a parathyrotoxic crisis, ultrasonography allows preoperative localisation of
who benefit from lowering of calcium levels before solitary adenomas in 75–90% of the patients. Better
parathyroidectomy. These patients need aggressive fluid localisation techniques have generated a move to-
replacement, correction of electrolyte imbalance, and wards less invasive surgery. Currently, focused para-
forced diuresis. For severe hypercalcaemia, refractory thyroidectomy (minimal incision, adenoma excision,
to these initial measures, intravenous bisphosphonates and no identification of the normal glands) can be
should be administered. Asymptomatic, mild, and mod- done in 60–75% of all patients with sporadic primary
erate primary hyperparathyroidism should not be treated hyperparathyroidism. Focused or selective parathyroid-
medically. If, for whatever reason, surgery cannot be done, ectomy has been shown in randomised trials to
yearly surveillance is advisable, with good hydration, lower the risk of postoperative hypocalcaemia and to
mobility, and a regular calcium dietary supply.6 reduce operation time compared with bilateral neck
Parathyroidectomy is the only curative treatment for the exploration, with excellent success rates.7–9 For patients
disease. For patients with asymptomatic primary hyper- with inconclusive localisation studies or suspected multi-
parathyroidism, agreed indications for surgical treatment glandular disease, bilateral parathyroid exploration is
the procedure of choice.
Most commonly, focused parathyroidectomy is done
Panel: Disorders in which serum calcium should be
under general anaesthesia, through a small lateral
routinely checked
or central neck incision. Patients are discharged on
• Renal lithiasis (calcium)
the same day or after an overnight stay. Variations of
• Osteoporosis
• Chondrocalcinosis the procedure include endoscopic or video-assisted
• Arterial hypertension approaches, local anaesthesia with early (<4 h) discharge,
• Cardiovascular disease and radioguided surgery. All of these procedures are
• Peptic ulcer being prospectively assessed.
• Pancreatitis of all types
To improve the results of adenomectomy, quick
• Functional abdominal symptoms
• Acute or chronic mental disturbances intraoperative measurement of serum PTH has been
• Postmenopausal women recommended,10 and is currently the focus of much
• Hypophyseal and pancreatic endocrine tumours (multiple investigation. Because the half-life of PTH is 3–5 min,
endocrine neoplasia 1) serum PTH can be expected to drop soon after focused
• Medullary carcinoma of the thyroid and
parathyroidectomy if no other diseased gland is present.
phaeochromocytoma (multiple endocrine neoplasia type 2a)
The most used and tested criteria for cure calls for a drop

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Comment

of serum PTH values, 10 min after adenoma resection, of left ventricular wall-thickness.18 In agreement with
of at least 50% below the highest previous value (either these findings, risk of myocardial infarction increases up
at induction of anaesthesia or pre-excision). Two recent to 10 years before surgery and declines to a normal level
reports11,12 indicate that patients with a single adenoma more than 1 year after parathyroidectomy.19
localised by concordant imaging (ultrasonography and
scintigraphy) might be operated on successfully without *Antonio Sitges-Serra, Anders Bergenfelz
intraoperative assay of PTH. Gawande and colleagues Department of Surgery, Hospital del Mar, 08003 Barcelona, Spain
(AS-S); and Lund University Hospital, Lund, Sweden (AB)
reported 322 consecutive focused parathyroidectomies
asitges@imas.imim.es
in patients with concordant imaging studies.11 In only
We declare that we have no conflict of interest. AS-S has a 4-year grant for his
three cases did the quick intraoperative assay of serum research from AGUR (Agència de Gestió d’Ajuts Universitaris i de Recerca,
PTH identify additional diseased glands. In three of #2005SGR 00961).
1 Wermers RA, Khosla S, Atkinson EJ, et al. Incidence of primary
the remaining patients, primary hyperparathyroidism hyperparathyroidism in Rochester, Minnesota, 1993–2001: an update on
persisted despite an appropriate drop in serum PTH. the changing epidemiology. J Bone Miner Res 2006; 21: 171–77.
2 Lundgren E, Hagström EG, Lundin J, et al. Primary hyperparathyroidism
The variables associated with postoperative hypo- revisited in menopausal women with serum calcium in the upper normal
calcaemia include: preoperative serum calcium above range at population-based screening 8 years ago. World J Surg 2002; 26:
931–36.
3·0 mmol/L, multiple gland excision, increased alkaline 3 Vestergaard P, Mollerup CL, Frokjaer VG, Christiansen P, Blichert-Toft M,
phosphatase, and reoperative and bilateral surgery. Mosekilde L. Cohort study of risk of fracture before and after surgery for
primary hyperparathyroidism. BMJ 2000; 321: 598–602.
Patients at risk of developing postoperative hypocalcaemia 4 Coker L, Rorie K, Cantley L, et al. Primary hyperparathyroidism, cognition,
and health-related quality of life. Ann Surg 2006; 242: 642–50.
should be given oral calcium (1–3 g or calcium ion daily)
5 Silverberg SJ, Bilezikian JP. “Incipient” primary hyperparathyroidism: a
with or without calcitriol (0·5–1 μg daily). “forme fruste” of an old disease. J Clin Endocrinol Metab 2003; 88: 5348–52.
6 Bilezikian JP, Potts JT Jr, Fuleihan Gel-H, et al. Summary statement from a
Parathyroidectomy improves neuromuscular symp- workshop on asymptomatic primary hyperparathyroidism: a perspective
toms and quality of life, decreases bone turnover,13 for the 21st century. J Clin Endocrinol Metab 2002; 87: 5353–61.
7 Bergenfelz A, Lindblom P, Tiblin S, Westerdahl J. Unilateral versus bilateral
increases bone mineral density, and halts renal lithiasis,14 exploration for primary hyperparathyroidism. Ann Surg 2002; 236: 541–51.
but does not reverse long-standing arterial hypertension, 8 Bergenfelz A, Kangiesser V, Zielke A, Nies C, Rothmund MM. Conventional
bilateral exploration versus open minimal invasive parathyroidectomy under
chondrocalcinosis, soft-tissue calcifications, or renal local anesthesia for primary hyperparathyroidism. Br J Surg 2005; 92: 190–07.
failure. In postmenopausal women with primary hyper- 9 Russell CF, Dolan SJ, Laird JD. Randomized clinical trial comparing
scan-directed unilateral versus bilateral cervical exploration for primary
parathyroidism, parathyroidectomy increases bone- hyperparathyroidism due to solitary adenoma. Br J Surg 2006; 93: 418–21.
mineral density at all sites although the size of the effect 10 Carneiro DM, Irvin III GL. New point-of-care intraoperative parathyroid
hormone assay for intraoperative guidance in parathyroidectomy.
is variable (particularly at the lumbar spine) and difficult World J Surg 2002; 26: 1074–77.
11 Gawande AA, Monchik JM, Abbruzzese TA, Iannuccilli JD, Ibrahim SI,
to predict for an individual. Improvement is greater in Moore FD Jr. Reassessment of parathyroid hormone monitoring during
young patients and in those patients with preoperative parathyroidectomy for primary hyperparathyroidism after 2 preoperative
localization studies. Arch Surg 2006; 141: 381–84.
osteoporosis.15 After parathyroidectomy, a reduction in 12 Stalberg P, Sidhu S, Sywak M, Robinson B, Wilkinson M, Delbridge L.
fracture risk is already detectable at 1 year and persists Intraoperative parathyroid hormone measurement during minimally
invasive parathyroidectomy. J Am Coll Surg 2006; 203: 1–6.
at 10 years.3,16 VanderWalde and colleagues reported that 13 Steiniche T, Christiansen P, Vesterby A, et al. Primary hyperparathyroidism:
the 10-year fracture-free survival after a diagnosis of bone structure, balance, and remodeling before and 3 years after surgical
treatment. Bone 2000; 26: 535–43.
primary hyperparathyroidism was 73% in patients treated 14 Silverberg SJ, Shane E, Jacobs TP, Siris E, Bilezikian JP. A 10-year prospective
study of primary hyperparathyroidism with or without parathyroid surgery.
surgically compared with 59% in those just observed.16 N Engl J Med 1999; 341: 1249–55.
Fracture risk-reduction was greatest at the hip level. 15 Sitges-Serra A, Girvent M, Pereira JA, et al. Bone mineral density in
menopausal women with primary hyperparathyroidism before and after
An improvement is also seen in fine variables of parathyroidectomy. World J Surg 2004; 28: 1148–52.
cardiovascular function investigated with echocardio- 16 VanderWalde LH, Liu ILA, O’Connell TX, Haigh PI. The effect of
parathyroidectomy on bone fracture risk in patients with primary
graphy during exercise, such as reduction of maximum hyperparathyroidism. Arch Surg 2006; 141: 885–91.
blood pressure, ST-segment depression, and ventricular 17 Nilsson IL, Aberg J, Rastad J, Lind L. Maintained normalization of
cardiovascular dysfunction 5 years after parathyroidectomy in primary
extrasystolic beats.17 A higher prevalence of left hyperparathyroidism. Surgery 2005; 137: 632–38.
18 Piovesan A, Molineri N, Casasso F, et al. Left ventricular hypertophy in
ventricular hypertrophy has also been seen in primary primary hyperparathyroidism. Effects of successful parathyroidectomy.
hyperparathyroidism compared with controls, even Clin Endocrinol (Oxf) 1999; 50: 321–28.
19 Vestergaard P, Mollerup CL, Frokjaer VG, Christiansen P, Blichert-Toft M,
when adjusted for the presence of arterial hypertension. Mosekilde L. Cardiovascular events before and after surgery for primary
Parathyroidectomy resulted in a measurable decrease hyperparathyroidism. World J Surg 2003; 27: 216–22.

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