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Holzheimer RG, Mannick JA, editors. Surgical Treatment: Evidence-Based and Problem-Oriented. Munich: Zuckschwerdt; 2001.

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Surgical Treatment: Evidence-Based and Problem-Oriented.

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Primary hyperparathyroidism

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Primary hyperparathyroidism (HPT) has been increasingly diagnosed since the mid 70's when automated laboratory methods first allowed measurement of serum calcium on wide indications (1). There is still variability in prevalence world wide, however in countries where recognition is inefficient, patients tend to present with more severe disease, larger parathyroid tumors and the obvious classical symptoms of parathyroid bone disease or a renal stone disorder and renal impairment. In countries with efficient diagnosis an increasing number of patients have presented with less severe hypercalcemia and non-classical symptoms, with psychiatric disability, weakness and fatigue. It has been debated whether patients with the mildest forms of HPT and non-traditional symptoms really benefit from surgery, or if they may just as well be managed conservatively with follow-up by internists (2).

Definition, pathogenesis, and epidemiology

Primary HPT is due to deficient regulation of parathyroid hormone (PTH) release in single or multiple parathyroid tumors with resulting increased PTH secretion and raised serum calcium values.

Primary HPT may be caused by parathyroid adenoma (85–90%), parathyroid chief cell hyperplasia (10–15%), water clear cell hyperplasia (today an exceedingly rare diagnosis), or parathyroid carcinoma, which in most developed countries, where primary HPT is common, accounts for no more than 0,5%. Parathyroid adenomas are monoclonal neoplasms, as is apparently also a majority of individual glands in chief cell hyperplasia. Genetic studies have revealed that 5% of parathyroid adenoma harbor a PRAD 1 (parathyroid adenoma) gene rearrangement, whereby the PTH promoter by chromosomal inversion has become localized adjacent to the cyclin D1 gene with resulting stimulation of proliferation (3). 30% of sporadic parathyroid adenoma have allelic loss combined with somatic mutation of the multiple endocrine neoplasia type 1 (MEN 1) menin gene. Allelic loss has also been demonstrated on other chromosomes, e.g., chromosomes 1, 6, 11, 15, and others, suggesting that other putative tumor suppressor genes may be involved in parathyroid tumorogenesis (3). A subset of postmenopausal females, in whom primary HPT is particularly common, has demonstrated vitamin D receptor (VDR) polymorphisms with inefficient VDR transcription/or instability (4). This aberration may be important for the prevalent development of HPT in older age groups, possibly by conveying susceptibility to modest reduction of vitamin D. It is likely that different genetic abnormalities initiate growth of parathyroid tumors, and may cause either rapid or slow disease progression and variable degree of hypercalcemia (3). Secondary mutations seem to be common, and may possibly alter the disease course by causing stepwise increments in serum calcium.

The etiology of primary HPT is in many aspects inadequately clarified. Radiation exposure may have initiated tumor growth in a minority group of patients, with a delay of 15–20 years until the disease has been clinically obvious.

The epidemiology of HPT depends greatly on the efficiency of serum calcium screening in the population, but there may be geographical differences in distribution.

Few countries have reported the epidemiology of HPT. High prevalence has been demonstrated in a Swedish autopsy study and swedish health surveys, and was substantiated in a recent screening study with serum calcium among postmenopausal females subjected to mammography, where surgically verified HPT was found in 2.1% (5). The majority of patients in health surveys have had mild hypercalcemia, fewer have had serum calcium values above 2.70 mmol/l, and a minority has been normocalcemic or intermittently hypercalcemic. Studies from Sweden and the United States have demonstrated, that even with liberal indications for treatment, only one tenth of the expected patient population has been subjected to surgery, and not always the patients with the most severe disease (5). In Japan the incidence of HPT has appeared lower, whereas parathyroid carcinoma has been more common than in western countries. From India limited series of severely symptomatic HPT patients have been reported, a large proportion has had malignant parathyroid tumors. Part of this disparity is likely to reflect variably efficient screening and diagnosis of HPT, but probably also indicates actual geographic differences in disease prevalence and presentation. It has thus been claimed that some severe forms of HPT may be partly attributed to concomitant vitamin D deficiency.

In countries with high detection rate postmenopausal females have been most frequently diagnosed with HPT. In young patients, especially adolescents, where the disease otherwise is rare, the presence of a familial multiple endocrine neoplasia type 1 (MEN 1) syndrome should be suspected - as in any patient with (synchronous or asynchronous) multiglandular parathyroid involvement. Sporadic HPT occasionally occurs in children, in any such case familial hypocalciuric hypercalcemia (FHH) should be excluded.


Symptoms in HPT are either classical, e.g. a more or less severe bone disease or renal stones/renal impairment, or non-classical with psychiatric disability, weakness, fatigue and metabolic disturbances.

The majority of nowadays prevalent postmenopausal female patients with HPT have mild hypercalcemia and vague symptoms (1, 6). Many may even appear asymptomatic if typical non-classical symptoms of HPT are not actively searched for. These patients tend to have slow and extended disease course, generally with some increment in serum calcium over time. Serum calcium may even show tendency to normalize, whereas PTH values continue to increase, a pattern compatible with renal function impairment or concomitant vitamin D deficiency. A minor proportion (10–20%), generally the younger HPT patients, may have higher serum calcium at presentation, more frequently classical symptoms and more rapid progression, occasional patients may present with hypercalcemic crisis.

Bone symptoms: Among currently diagnosed patients the classical parathyroid bone disease, osteitis fibrosa cystica, with advanced demineralization and cystic bone lesions, has become exceedingly rare (1, 6). A minority group of patients with marked hypercalcemia may have raised alkaline phosphatases and subtle radiological bone changes, visible especially on the radial side of the middle phalanges and the distal clavicles. Loss of bone mineral may, however, generally, but not invariably, be revealed also in the common contemporary patients with moderate hypercalcemia, if more sensitive bone density measurements are applied (7, 8). The bone loss is a result of increased bone turnover and more evident in cortical bone of the distal radius and femoral neck than in trabecular bone of the spine (9). Whether bone loss is related to increased risk of fragility fracture has been debated, the risk for forearm fracture has appeared slightly increased. There may, however, be other contributing causes to loss of bone mineral in elderly females with HPT, such as oestrogen deficiency and possibly also relative lack of vitamin D. The bone loss has probably developed insidiously over a long period of time (1). Parathyroidectomy has been reported to result in increased bone density but the bone loss is generally only partially reversible (10).

Renal stones: Previously series of HPT patients used to report a renal stone incidence of 50% or more. Renal stones are rare in postmenopausal females with HPT and moderate hypercalcemia, and therefore the overall stone incidence in more recent series has often been no more than 10–20% (1, 6, 11). Renal stones are, however, still common in young male patients with HPT, and since surgery for HPT constitutes markedly efficient treatment, presence of this symptom is generally considered as a clear indication for parathyroid surgery, even in patients with mild hypercalcemia (1, 6).

Renal function impairment: Renal failure is currently an unusual complication of primary HPT. Some reduction of creatinine clearance and urinary concentration capacity can occur, even in patients with mild hypercalcemia.

Psychiatric symptoms: A psychiatric disability has been recognized as important part of the symptomatology of HPT (1, 6, 12, 13). Typically, the patients tend to have moderately intense depressive symptoms, neurasthenia, concentration difficulty, lassitude and fatigue. Albeit vague, these symptoms are typical and may be verified by objective psychiatric tests and life quality protocols, and can be incapacitating in patients with intellectual, challenging work (13). Elderly patients may be more sensitive, and present with confusional syndromes, especially if the hypercalcemia is marked. Improvement of the psychiatric disability can be expected after parathyroid surgery and may sometimes be impressive in patients with confusional syndromes, or in those with intellectual occupation, but randomized evaluation of such outcome is lacking (1, 6).

Marked neuromuscular weakness with atrophy of proximal muscle groups used to be a prominent symptom of HPT, but is currently exceedingly rare. Less pronounced weakness may be a typical complaint, possibly as part of a general fatigue (1, 6).

Metabolic disturbances and cardiovascular disease: HPT has been associated with risk factors for cardiovascular disease, such as impaired glucose tolerance, disturbed lipid metabolism, and increased incidence of hypertension (1, 6). The glucose intolerance tends to remain unaffected by parathyroid surgery, whereas the lipid disturbance may normalize. Parathyroid surgery seldomly affects hypertension, and some of these derangements may be indirectly associated. HPT also has been attributed to cardiac disturbance with left ventricular hypertrophy, myocardial and valvular calcifications, and electrocardiographic abnormalities, with possible improvement after parathyroid surgery (14). Increased serum urate concentrations may be found in HPT patients, with a general tendency to normalize after parathyroid surgery.

Long-term follow-up of surgically unattended mild hypercalcemia has revealed increased mortality in cardiovascular disease in individuals younger than 70 years (1, 6). Increased mortality has also been demonstrated in series of operated HPT patients, with a reported risk increase comparable to the effect of cigarette smoking (15, 16). The increased risk has been claimed to correlate to the extent of hypercalcemia, and to normalize by parathyroid surgery, but only in patients with less advanced disease (15, 16). The increased mortality was not evident in a series of more recently operated HPT patients.

Peptic ulcer is generally not associated with HPT, except in MEN 1 patients with the Zollinger-Ellison syndrome, although non-ulcer dyspepsia may be a distinct complaint. Pancreatitis is occasionally seen, sometimes in younger HPT patients, or as a serious complication of severe hypercalcemia.

Postmenopausal female patients with HPT generally have mild disease with vague symptoms, whereas younger individuals may have more rapidly progressive, clearly symptomatic disease.

Diagnosis of HPT

The diagnosis of HPT is based on demonstration of raised total albumin corrected serum calcium values combined with abnormally high values of intact PTH.

Ionized calcium measurements may be more sensitive for diagnosis of mild HPT, but routine application is hampered by rather extensive assay variations. Previously other causes of hypercalcemia had to be excluded by various investigations. The development of sensitive immunometric assays for intact PTH has markedly simplified and increased the accuracy of the diagnosis, which is now generally settled on an out-patient basis. It is important to emphasize that intact PTH values in the upper normal reference range together with hypercalcemia indicate HPT.


Surgery remains the recommended treatment in HPT and is generally undertaken with high success rate and low incidence of complications.

Comprehensive series of patients operated upon for primary HPT have revealed excellent results with a success rate in achieving normocalcemia of 95–98%. Less favorable results have been obtained when operations have been performed by less experienced surgeons. Classical complications, recurrent laryngeal nerve paralysis and hypoparathyroidism, should nowadays be unusual, 1% or less. The operation is rarely associated with mortality and morbidity is often exceedingly low. The patients may be managed with short hospital stay or on out patient basis, if serum calcium monitoring is adequate. Elderly patients and those with complicating diseases, essentially cardiac or respiratory insufficiency, may constitute higher risk groups, but can often be expediently managed with adequate pre- and peroperative care. The operation may be performed in local anesthesia. Patients with marked hypercalcemia prior to surgery should postoperatively be liberally substituted with calcium (and occasionally vitamin D) to prevent hypocalcemia which may cause cardiac arrhythmia.

The high success rate of parathyroid surgery has been a strong argument in favor of a liberal attitude towards active management. The indications for surgery in primary HPT have been debated, and were in a NIH Consensus statement considered to comprise all patients below 50 years of age, patients with a history of renal stones (even those with border-line hypercalcemia), bone mass lower than 2SD of the age and gender matched normal reference, creatinine clearance reduced by at least 30%, or a urinary calcium excretion increased above 400 mg/24 hours. Lack of prospective studies implies that recommended indications for surgery vary, but these should in our opinion include also patients with apparent and typical psychiatric symptoms (including confusion in the elderly), as well as serum calcium concentrations increased above 2.70 (-2.80) mmol/l (table I). Higher serum calcium values or evident symptoms may be needed to justify operation in older persons or those with associated illness.

Table I. Indications for surgery in primary HPT.

Table I

Indications for surgery in primary HPT.

A conservative surgical strategy implying routine visualization of all four parathyroid glands with bilateral neck exploration, excision of only enlarged glands and avoiding biopsies of normal-sized glands, has been considered important for the favorable results of parathyroid surgery. Unilateral parathyroid exploration may, however, also be successfully applied for excision of single adenoma. Recently improved methods of localizing parathyroid glands prior to surgery by MIBI-scintigraphy and a rapid intraoperative PTH test, which may verify excision of all pathological glands, may further support the unilateral procedure. For cosmetic reasons a direct, minimally invasive or endoscopic approach may be undertaken in selected patients with high serum calcium values and preoperatively localized glands (18, 19). Undiagnosed MEN 1 cases may be failures in incomplete explorations due to a general markedly asymmetrical multiglandular enlargement.

A conservative surgical strategy in HPT implies excision of only enlarged parathyroid glands, and no general biopsies of overtly normal glands. Preoperative localization of diseased glands with MIBI-scintigraphy and a rapid intraoperative PTH test may allow unilateral, minimally invasive or endoscopic operation for single adenoma.

Non-operative surveillance

There is presently no efficient medical treatment in HPT, although oestrogen may improve bone mineralization in selected patients. The NIH Consensus statement suggested that a group of HPT patients with mildly elevated serum calcium values and no clearly disease related symptoms could be expected to follow a benign course, and could possibly be managed non-operatively (1, 2, 20). This has been disputed since studies reporting surveillance in patients with primary HPT have been few and hampered by lack of compliance and often limited follow-up. Long-term surveillance without surgery entails a risk to result in reduced physical and intellectual capacity or confusion in the elderly, and has only been proven safe in patients with border-line hypercalcemia (1). Consequently it seems appropriate to recommend non-operative surveillance in elderly persons without symptoms or complications of the disease, who exhibit serum calcium values below or around 2.70 mmol/l, but prospective evaluation is needed to evaluate this treatment option.


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Copyright © 2001, W. Zuckschwerdt Verlag GmbH.
Bookshelf ID: NBK7007


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