Symptoms presented by patients suffering from PHPT result from excess mobilization of osseous calcium phosphate and hypercalcemia. Colloquially, they are often summed up with "stones, bones, abdominal groans and psychic moans" or similar expressions.

Here, stones refers to nephrolithiasis, nephrocalcinosis and nephrogenic diabetes insipidus. Patients may report polyuria and consecutive polydipsia. In severe cases, renal failure may occur.

PHT stimulates osteoclast activity and continuously increased levels of this hormone lead to loss of bone mass. Osteitis fibrosa cystica is classically associated with PHPT and is characterized by replacement of decomposed bone with fibrous tissue. Cysts are recognizable on radiographic images and may turn into so-called brown tumors, which are not true neoplasms. Osteopenia, osteoporosis and osteomalacia have also been described in PHPT patients.

Hypercalcemia stimulates gastrin and subsequently gastric acid production. Therefore, nausea, vomiting, peptic ulcers and abdominal pain are common symptoms of PHPT [10]. Constipation is frequently observed but does not seem to be triggered by hypercalcemia [11]. In some case, PHPT has been related to pancreatitis.

Electrolyte imbalances presumably also account for neuropsychiatric symptoms. Patients may present with reduced awareness, memory impairment, depression or psychosis.

Additionally, malaise, fatigue and muscle weakness are characteristic for this disease.

Laboratory analyses of blood samples typically reveal increased levels of PTH, hypercalcemia, hypophosphatemia and augmented alkaline phosphatase levels. Serum 25-hydroxyvitamin D concentrations are not altered in PHPT. Urine analysis shows high levels of phosphate and most commonly elevated levels of calcium. The extent of abnormal findings does not necessarily correlate with severity of symptoms [11].

Patients may present comorbidities and employ medication to treat them. Distinct compounds may modulate calcium homeostasis and simulate PHPT. Thiazide diuretics reduce renal calcium excretion and lead to increased serum calcium levels. If at all possible, such medication should be stopped two weeks before obtaining blood and urine samples from a patient suspicious for hyperparathyroidism. Other iatrogenic causes of hypercalcemia are long-term lithium treatment, tamoxifen administration and intake of oral contraceptives.

In order to diagnose PHPT, repeated measurements have to be performed and pathological findings need to be reproducible. This is of particular importance since any deviation from the characteristic pattern of findings may indicate another disease. Secondary hyperparathyroidism, for instance, is related to hypocalcemia and hyperphosphatemia but also to augmented PTH concentrations. Vitamin D deficiencies or renal insufficiency may account for these symptoms. Tertiary hyperparathyroidism is associated with increased levels of PTH, hypercalcemia and hyperphosphatemia.

Diagnostic imaging is not required for diagnosing PHPT. However scintigraphy may be very helpful to localize the lesion and to distinguish single tumors from hyperplasia or multiple adenomas and this information is of great value when preparing minimally invasive surgery [12]. Indeed, lack of response to minimally invasive surgery commonly results from undetected multiple parathyroid gland involvement. Scintigraphic examination may be combined with sonography or magnetic resonance imaging.

Additionally, pre-operative bone scans not only allow for an assessment of osseous lesions, but also permit an estimation of post-operative hypocalcemia. They may also provide important information to support a decision for or against surgery [13].

Watchful waiting is indicated for asymptomatic patients with mild electrolyte imbalances, conserved renal function and minimal loss of bone mass. These patients should, however, undergo regular follow-ups to detect disease progress as early as possible. In this line, blood samples should be analyzed twice a year for calcium and phosphate levels as well as renal parameters. Bone scans should be performed in longer intervals. In order to delay or avoid disease progress, treatment of comorbidities with medication that aggravates hypercalcemia should be re-considered, possibly reduced or replaced. Patients should be advised to maintain appropriate hydration and to keep a diet with moderate calcium content. About 1 g per day is recommended. These measures may help to prevent nephrolithiasis without stimulating PTH production. Physical activity is highly recommended to strengthen the muscles that support the weakened skeleton.

Mild cases may also indicate drug therapy. Electrolyte imbalances should be adjusted and such measures will also protect the kidneys. Osseous lesions may be treated with inhibitors of bone resorption, e.g. with biphosphonates.

Symptomatic patients are usually recommended for surgery. Parathyroidectomy is the treatment of choice and should be carried out after localizing all sites of tissue alterations. Single adenoma may be resected in a minimally invasive approach, but this is often not possible in case of hyperplasia or multiple adenomas. Here, open surgery needs to be carried out. It is not necessary to remove parathyroid glands that don't show any pathological alteration.

Parathyroidectomy is considered a safe and successful surgical procedure. Cure rates exceed 95% and complications rarely occur. Post-operative hypocalcemia is likely, but more frequently result from bone repair processes than from an absolute lack of PTH. Hemorrhages have been described and patients may claim transient raucousness.

Of note, ectopic parathyroid tumors have been reported. If PTH levels do not drop after parathyroidectomy, the possibility of ectopic, endocrinologically active tissues should be considered. They may be identified in imaging studies and require surgical removal. They are not necessarily located in close proximity to the parathyroid and thyroid glands.

Follow-ups consist in analyses of blood samples to assure physiological serum levels of PTH and electrolytes as well as bone density measurement about one year after surgery.

In general, prognosis for PHPT is good. Parathyroidectomy is the treatment of choice to normalize electrolyte concentrations and bone density, is related to high cure rates, but may not even be required in asymptomatic patients [8] [9]. Regular follow-ups should be realized to detect possible disease progress if an initial decision against surgical intervention is taken. Age seems to be a favorable prognostic factor and young patients are at higher risk of disease progress and the need for parathyroidectomy.

Electrolyte imbalances may trigger fatal cardiovascular accidents.

The majority of PHPT cases, an estimated 85%, is caused by a single parathyroid adenoma. A significant share of patients, approximately 15% of all cases, presents with hyperplasia or multiple adenomas. Parathyroid cancer is rare and seems to account for about 1% of PHPT cases [2].

The etiology of parathyroid tumors and hyperplasia is not fully understood. Genetic predisposition and epigenetic mechanisms have been proposed to increase the individual risk of developing sporadic PHPT [1]. In contrast, high familial incidence does definitely result from genetic disorders. In this context, the disease may be diagnosed in patients suffering from familial isolated hyperparathyroidism, hyperparathyroidism-jaw tumor syndrome, familial benign hypocalciuric hypercalcemia and its more severe, homozygous form neonatal severe hyperparathyroidism [3], or any multiple endocrine neoplasia syndrome.

Data regarding incidence and prevalence of the disease may be underestimated due to an unknown, but presumably high number of asymptomatic patients [4]. Keeping this limitation in mind, the annual incidence of PHPT has been estimated to be about 2 per 10,000 individuals [5]. While the overall prevalence amounts to approximately 0.1%, there are significant differences between males and females. Prevalence in women is up to 4-fold higher than prevalence in men. Indeed, postmenopausal women account for the greatest share of patients and PHPT is the most common cause for hypercalcemia in this group of patients [6]. PHPT may rarely be diagnosed in children and adolescents. Most patients are diagnosed with this endocrinological disorder during their sixth decade of life.

Under physiological conditions, calcium, phosphate and regulatory hormone concentrations are tightly regulated. Negative feedback is the main mechanism behind such regulation and in this context, PTH expression and release should diminish upon:

• Increased serum calcium levels
• Decreased phosphate concentrations
• Augmented calcitriol synthesis

These are precisely the effects of PTH production stimulation.

In PHPT, down-regulation of PTH synthesis is impaired. Parathyroid tumors presumably present anomalies in sensing serum calcium levels or in intracellular transduction pathways. In cases of parathyroid hyperplasia, an abnormally high number of endocrinologically active cells seems to contribute to PHPT symptoms, too.

PTH counteracts low calcium levels by mobilization of calcium phosphate from osseous tissue. Although this assures rapid elevation of available calcium amounts, in the long term, it will cause osteopenia. In PHPT patients, extensive loss of bone mass cannot be compensated by calcitriol-mediated bone formation. In severe cases, affected individuals may develop osteitis fibrosa cystica.

Continuously increased serum calcium levels combined with an enhanced re-absorption in distal tubuli of the kidney may lead to exceedance of the solubility products of calcium salts and subsequent formation of renal calculi.

Hypercalcemia and hypophosphatemia are characteristic yet not specific for PHPT. They may be associated with fatigue, muscle weakness, loss of appetite, nausea, peptic ulcers and neuropsychiatric symptoms [7].

No preventive measures can be recommended against sporadic PHPT. Family members of patients suffering from genetic disorders triggering hyperparathyroidism may benefit from regular blood analyses in order to detect pathological alterations early.

The parathyroid gland is a paired, endocrinological organ. Its name derives from its close proximity to the thyroid gland, although both organs work independently. The main function of the parathyroid gland is the synthesis and release of parathyroid hormone (PTH), one of the main modulators of calcium homeostasis.

In detail, PTH synthesis is stimulated by decreased serum calcium levels and elevated phosphate concentrations. The hormone induces rapid mobilization of calcium phosphate from the bones by increasing osteoclast activity. On the other hand, it augments calcium re-absorption and diminishes phosphate recovery in renal tubuli. Both processes contribute not only to augmented calcium availability, but also provoke a shift in calcium to phosphate ratios and thus further increase serum levels of unbound, ionized calcium.

PTH synthesis decreases to basal levels if serum calcium concentrations are in their physiological range. Also, it promotes calcitriol synthesis and calcitriol, in turn, inhibits PTH production. Calcitriol enhances intestinal calcium and phosphate absorption and stimulates bone formation. These regulatory mechanisms prevent an excess production of PTH, hypercalcemia, hypophosphatemia and loss of bone mass.

However, if regulation fails because of primary hyperparathyroidism (PHPT), i.e., because of an intrinsic lesion of the parathyroid gland, these pathological conditions will manifest. The precise combination of altered endocrinological and electrolyte parameters allows diagnosis of PHPT and helps to distinguish this disease from secondary or other forms of hyperparathyroidism. Neoplasms, mainly benign adenoma, are the main causes of PHPT. Furthermore, genetic predisposition and irradation may account for this disease or contribute to tumor development [1].

The parathyroid glands are small, endocrinologically active organs in close proximity to the thyroid gland. Their main functions are synthesis and release of parathyroid hormone (PTH). This hormone plays a major role in maintaining calcium homeostasis. In detail, PTH is stimulated by low serum calcium levels and counteracts by rapidly mobilizing osseous calcium phosphate and by decreasing renal calcium excretion and phosphate recovery.

Under normal circumstances, this results in physiological calcium and phosphate concentrations that inhibit further PTH synthesis by means of negative feedback mechanisms. However, in cases of primary hyperparathyroidism (PHPT), these regulatory mechanisms do not work very well because PTH production persists independent of inhibitory factors.

Causes

The vast majority of PHPT patients suffers from either a single or multiple benign tumors of the parathyroid glands. Less than 1% of all cases results from a malignant neoplasm of this organ.

In rare cases, genetic disorders account for this disease.

Symptoms

Because the above described regulatory mechanisms fail, PHPT patients present with elevated PTH levels, increased serum calcium concentrations, diminished phosphate levels and osseous lesions. They are often summed up in the expression "stones, bones, abdominal groans and psychic moans":

• "Stones" refers to renal calculi due to excess calcium re-absorption.
• "Bones" describes a loss of bone mass that results from mobilization of calcium phosphate.
• "Abdominal groans" may be uttered because of nausea, vomiting, gastric ulcers, constipation and abdominal pain.
• "Psychic moans" refers to neuropsychiatric symptoms of hypercalcemia, i.e., reduced awareness, memory impairment, depression or psychosis.

Diagnosis

Diagnosis of PHPT is based on the results of blood and urine samples. Measurements have to be repeated in order to avoid erroneous diagnoses due to momentary hormonal or electrolyte imbalances.

Scintigraphic examinations may be carried out to localize and quantify parathyroid lesions.

Treatment

Mild, asymptomatic cases may just require regular follow-ups to detect possible disease progress as early as possible. Drug therapy may be employed to correct electrolyte imbalances, to prevent renal disorders and for inhibition of bone resorption.

Patients presenting with symptoms of low bone density or hypercalcemia are usually recommended for surgical resection of altered parathyroid tissue. In many cases, this surgical intervention can be realized with minimally invasive techniques.

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