Incidence

Early in the history of PHP, patients presented with manifestations of severe hypercalcaemia and advanced disease, but the true incidence of hyperparathyroidism was not known due to the inability to routinely measure serum calcium levels. The development of the automated serum chemical analyser and the practice of widespread biochemical screening permitted the detection of mild increases in serum calcium levels, thereby allowing earlier recognition of abnormalities in calcium homeostasis.

Multiple factors influence the incidence of PHP, including the region of the world under evaluation, the nutritional status of the studied population, iatrogenic factors and the availability of routine biochemical screening.

In the 1970s, there was a dramatic fivefold increase in the incidence of PHP, largely due to the ‘catch-up’ effect of identifying patients who had PHP prior to the development of the automated calcium analyser. During the 1980s, the incidence of PHP in North America actually decreased as the impact of the ‘catch-up’ effect levelled off.

The number of patients with a history of irradiation to the head and neck region for benign disorders decreased in the 1980s, which may also have contributed to the decreased incidence of PHP, as head and neck irradiation is a known risk factor for parathyroid hypersecretion.

PHP occurs more frequently in women than men, but the overall incidence increases with age in both sexes. In North America, the incidence of PHP in the general population is 4.3 per 1000, whereas in Europe the incidence is 3 per 1000. In women aged between 55 and 75 years, the incidence of PHP is 21 per 1000. Possible explanations for the increased incidence with age include the lower rate of biochemical screening in patients less than 50 years of age and the increased use of bone density measurements in postmenopausal women as a routine part of healthcare screening. The detection of osteopenia and/or osteoporosis that is out of proportion to age-matched controls often leads the clinician to measure serum calcium and PTH levels, thereby identifying hyperparathyroidism as the cause of increased bone loss. Vitamin D deficiency also influences the true detected incidence of PHP as this condition may cause serum calcium levels to be normal in patients with hyperparathyroidism. For example, the incidence of vitamin D deficiency in southern Europe is high, leading to an underestimation of the true incidence of hyperparathyroidism in this region of the world.

Clinical manifestations

The clinical presentation of patients with PHP is highly variable, ranging from none to profound symptoms of hypercalcaemia, such as excessive thirst, dehydration, kidney stones, muscle weakness and pathological fracture. Generally, the clinical manifestations of PHP can be broadly classified by organ system ( Box 1.1 ). Since many of these symptoms overlap with other clinical conditions, particularly in the elderly, the diagnosis of hyperparathyroidism is often delayed until hypercalcaemia is recognised on biochemical screening. Often the presence of a classic symptom, such as nephrolithiasis, will lead the astute clinician to assess the patient for PHP. By far, fatigue is one of the most common symptoms of hyperparathyroidism, being present in > 80% of patients. Numerous studies have shown that a high percentage of patients that are thought to be asymptomatic actually have occult symptoms attributable to PHP.

There are numerous medical conditions that are associated with and/or exacerbated by PHP, including hypertension, diabetes, pancreatitis, nephrolithiasis, gout and peptic ulcer disease.

Diagnosis

Prior to the 1970s and the advent of routine serum calcium measurements as part of the basic metabolic profile, the diagnosis of PHP was made primarily on clinical findings. Walter St Goar immortalised this constellation of findings in the mnemonic ‘bones, stones and groans’. However, with routine serum calcium measurements, an elevated serum calcium level has become the most common presentation. PHP is confirmed by elevated serum calcium and serum PTH levels and can be suggested by other laboratory values (see below):

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  Elevated serum calcium. While a useful screening tool, many conditions can lead to inaccuracies in the measured total serum calcium levels. For example, hypoalbuminaemia and acidosis can create ‘normal’ serum calcium levels. Given these variables, many groups favour measuring the ionised serum calcium level instead. Monchik found in a number of series that an elevated serum ionised calcium correlated better with the presence of PHP as confirmed by surgery.

  
  
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  Elevated serum PTH. Current antibody-driven assays for serum intact parathyroid hormone (iPTH) levels are highly accurate.

  
  
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  Chloride:phosphate ratio. A recent retrospective study suggests that a chloride:phosphate ratio ≥ 33 is indicative of PHP in both hypercalcaemic and normocalcaemic patients.

  
  
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  Hypercalciuria. The presence of hypercalciuria rules out benign familial hypercalcaemic hypocalciuria, which can mimic PHP.

  
  
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  Hypophosphataemia. Due to the decreased resorption of phosphate by the renal tubule, phosphate levels decrease in approximately 50% of patients with PHP.

Normocalcaemic hyperparathyroidism

There is a small subset of patients with PHP who present with normal or only intermittently elevated calcium levels. Mather first described normocalcaemic hyperparathyroidism in 1953 in a woman who presented with osteitis fibrosa cystica. Since that time, this variation of PHP has been an infrequent but recognised entity. While still uncommon when compared with hypercalcaemic PHP, recent population studies have shown that this variant of the disease may be more prevalent than previously believed and that improved screening may help identify mildly symptomatic or asymptomatic patients.

The exact biochemical mechanisms of normocalcaemic PHP remain elusive. Some investigators postulate that the normocalcaemic variant of PHP represents an early or preclinical phase that progresses to typical hypercalcaemic PHP. Others have found distinct differences in the biological response to PTH in patients with normocalcaemic vs. hypercalcaemic hyperparathyroidism. For example, Maruani et al. found that patients with normocalcaemic hyperparathyroidism displayed a resistance to the renal and bony effects of PTH as measured by a lower fasting urine calcium excretion and renal tubular calcium resorption, as well as lower values of markers of bone turnover.

While most patients with normocalcaemic PHP present with nephrolithiasis, recent data show that other classic constitutional symptoms are just as prevalent in normocalcaemic patients as in hypercalcaemic PHP patients, suggesting that there is a larger unidentified population with PHP.

The majority of patients with normocalcaemic PHP present with renal calculi and hypercalciuria. However, the most common cause of renal calculi and hypercalciuria is idiopathic hypercalciuria (IH). To further confound the matter, some variants of IH have elevated PTH levels. It is vitally important to distinguish between these two entities since surgical parathyroidectomy effectively cures normocalcaemic PHP, whereas postsurgical IH patients continue to form stones.

Many tests are helpful in differentiating between the two diseases, but none has been shown to be conclusive enough to be used in isolation. The best diagnostic yield is to use two or more tests in combination:

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  Thiazide administration. Administration of thiazide diuretics leads to a decrease in urinary calcium excretion. Patients with normocalcaemic PHP will have persistently elevated PTH levels, whereas those with IH will have a normalisation of PTH.

  
  
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  Phosphate deprivation. After restricting phosphate to 350 mg/day and administering 650 mg of aluminium hydroxide four times a day (while on a normal calorie and normal calcium diet), serum calcium and phosphorus levels are checked every day for 4 days. Patients with subsequent hypercalcaemia or persistent hypercalciuria usually have normocalcaemic PHP. This test is no longer used routinely.

  
  
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  Calcium loading test. After administration of either 350 or 1000 mg of oral calcium, serum calcium and urine calcium are measured. Patients with normocalcaemic PHP have a significant increase in serum calcium (due to increased intestinal absorption) and an increase in urine calcium excretion, whereas intestinal absorption of calcium varies widely in patients with IH. In a recent study, after administration of 1 g of oral calcium, the combined parameters of (i) circulating PTH nadir (pg/mL) × peak calcium concentration (mg/dL) and (ii) relative PTH decline/relative calcium increment diagnosed normocalcaemic PHP with 100% sensitivity and 87% specificity. Furthermore, calcium loading suppressed urinary cyclic AMP but did not suppress PTH levels below 70% of baseline.

  
  
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  Serum ionised calcium. An elevated ionised calcium, in conjunction with an elevated PTH, is increasingly gaining acceptance as an excellent means of distinguishing normocalcaemic PHP from IH.

As mentioned previously, the mainstay of treatment for normocalcaemic PHP is operative parathyroidectomy.

Hypercalcaemic crisis

Hypercalcaemia is seen in approximately 0.5% of the general population and up to 5% of the hospital population. The majority of cases of hypercalcaemia are classified as mild to moderate (< 12 or 12–14 mg/dL respectively) and the patient is asymptomatic. This group responds to dietary measures and treatment of the underlying aetiology. However, a subset of patients will present in hypercalcaemic crisis, with serum calcium > 14 mg/dL, and are severely symptomatic. These patients require hospitalisation and aggressive reduction of serum calcium. Fortunately, except in cases of malignancy, treatment for hypercalcaemia is typically successful.

Since the calcium ion plays a crucial role in membrane potentials throughout the body, the symptoms of hypercalcaemia are varied and potentially life-threatening. The classic presentation of severe hypercalcaemia includes acute confusion, abdominal pain, vomiting, dehydration and anuria. In addition, patients may develop lethal arrhythmias due to decreased conduction velocities and shortened refractory periods, which manifest on an electrocardiogram as a prolonged P–R interval, a shortened Q–T interval, and arrhythmia. Hypercalcaemic crisis is the most extreme form of hypercalcaemia and is defined as severe hypercalcaemia in association with profound dehydration and obtundation. At serum calcium levels of 15–18 mg/dL, coma and cardiac arrest may occur.

The most common aetiology of hypercalcaemia in non-hospitalised patients is PHP, while malignancy accounts for almost two-thirds of the hypercalcaemic inpatient population. It is crucial to identify the underlying cause of hypercalcaemia in order to effectively and definitively address the acute event. Box 1.2 lists the differential diagnoses for hypercalcaemia. The treatment of severe hypercalcaemia revolves around aggressive rehydration, increasing renal excretion of calcium, blunting of calcium release from skeletal stores, and treating the underlying cause of the hypercalcaemia.

The primary goal of treatment is to achieve adequate volume resuscitation, which in turn increases calcium excretion in the kidneys. Patients are invariably dehydrated due to poor oral intake and vomiting. The resultant decrement in glomerular filtration rate leads to a decrease in renal excretion of calcium. Typically, 200–500 mL/h of normal saline are given to maintain urine output above 100 mL/h, with the caveat that comorbidities may limit the rate of resuscitation. Using normal saline lends substrate for the resultant natriuresis. Once the intravascular volume is restored, loop diuretics such as furosemide may be given to enhance calciuresis by inhibiting calcium resorption in the thick ascending limb of the loop of Henle. During the resuscitative phase, the patient must be monitored closely for signs of fluid overload, hypokalaemia and hypomagnesaemia. Serum calcium levels can be reduced by 1.6–2.5 mg/dL within 24 hours by volume repletion and loop diuretic administration alone. However, when serum calcium exceeds 12 mg/dL or hypercalcaemia is caused by malignancy, intravenous fluids and diuretics alone are usually insufficient to normalise calcium levels.

Numerous agents are available to blunt the release of calcium from bone resorption and treat the underlying disease. Table 1.1 provides an overview of agents available to combat hypercalcaemia and their relative strengths and weaknesses.

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  Bisphosphonates: pamidronate 60–90 mg i.v. Bisphosphonates are pyrophosphate analogues that are concentrated in areas of high bone turnover and inhibit osteoclast activity. Endogenous phosphatases cannot hydrolyse the central carbon–phosphorus–carbon bond, making this drug stable in vivo. Bisphosphonates should be given intravenously due to their poor absorption by the gastrointestinal tract. In the USA, only etidronate (first generation) and pamidronate (second generation) are approved for use in treating hypercalcaemia. Pamidronate has widely supplanted etidronate as the bisphosphonate of choice due to its faster onset, increased duration of action, increased efficacy and minimal adverse effect on mineralisation. One dose of intravenous pamidronate normalises serum calcium for 10–14 days in 80–100% of patients with hypercalcaemia of malignancy. Newer, more potent generations of bisphosphonates may replace pamidronate as the standard as more clinical data become available.

  
  
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  Calcitonin: salmon calcitonin 4–8 U/kg s.c./i.v. Calcitonin diminishes osteoclast activity and increases calciuresis within minutes of administration. However, the duration of action is limited to only a few days. Calcitonin therapy only rarely results in normocalcaemia. Tachyphylaxis limits the long-term use of calcitonin. Currently, calcitonin is used primarily as an immediate hypocalcaemic agent that temporises until the more sustained effects of other agents begin.

  
  
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  Gallium nitrate: 200 mg/m ² i.v. q.d. for 5 days. Gallium nitrate inhibits bone resorption by reducing the solubility of hydroxyapatite crystals. This drug induces normocalcaemia within 2–3 days that lasts for 5–6 days in approximately 75% of patients. The use of gallium nitrate has been limited by its nephrotoxicity, the need for continuous infusion and lack of clinical data.

  
  
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  Plicamycin: 25 μg/kg. Plicamycin is an osteoclast cytotoxin originally used in chemotherapy. Due to its serious side-effects (hepatic, renal and bone marrow toxicity), plicamycin is reserved for patients who fail bisphosphonate therapy. Since toxicities are related to the frequency and total dosage, administration is limited to one dose, with additional dosing only if hypercalcaemia recurs.

  
  
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  Glucocorticoids: prednisone 40–100 mg p.o. q.d. or hydrocortisone 200–300 mg i.v. for 3–5 days. Glucocorticoids are used primarily to augment the effect of calcitonin or in diseases associated with vitamin D excess (i.e. granulomatous diseases, vitamin D toxicity and multiple myeloma). Glucocorticoids increase calciuresis, decrease intestinal absorption of calcium and have a direct tumoricidal effect on certain haematological malignancies as well as breast cancer.

  
  
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  Oral inorganic phosphate: phosphate 1–1.5 g p.o. q.d. Oral inorganic phosphate has a limited effect in normalising serum calcium in patients who are hypophosphataemic by increasing calcium uptake by bone and intestinal absorption of calcium. Intravenous phosphate is one of the swiftest means to reduce serum calcium levels. However, it can cause fatal hypocalcaemia and severe organ failure by calcium phosphate precipitation. As such, intravenous phosphate is reserved for life-threatening hypercalcaemia, and even then must be used with extreme caution.

  
  
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  Dialysis. This is the treatment of choice for patients with hypercalcaemia and renal or heart failure. Dialysis may also be considered in hypercalcaemic patients who fail standard therapies. Haemodialysis and peritoneal dialysis can remove up to 250 mg of calcium/hour. Care must be taken to avoid the hypophosphataemia that often accompanies dialysis.

The underlying cause of hypercalcaemic crisis must always be addressed as part of the definitive management. In patients with an elevated PTH level and clinical factors suggestive of PHP, parathyroidectomy is the fastest way to decrease PTH levels and consequently serum calcium levels. Therefore, expedient operative intervention should always be considered in this subgroup of patients.

In contrast, patients with malignancy-associated hypercalcaemic crisis typically present at advanced or terminal stages of their disease with a mean survival of only months. In this setting, discussion with the patient and family regarding end-of-life decisions will be appropriate.

Surgical indications

The treatment of PHP is primarily surgical as medical interventions do not address the underlying pathology. Medical treatment is generally temporary and is reserved for acute hypercalcaemic crises or for patients who have mild disease with low risk of long-term sequelae or are poor operative candidates based on age or comorbidities. Definitive therapy is focused on removal of the offending gland or glands. Box 1.3 lists the current indications for surgery in PHP, which include (1) symptoms, (2) age less than 50, (3) significant hypercalcaemia, (4) osteoporosis and (5) decreased renal filtration. Recommendations for parathyroidectomy in asymptomatic patients were updated in 2008, as surgical intervention decreases the long-term risks of hypercalcaemia on bone health and nephrolithiasis in broad patient populations.

Imaging and localisation

In the hands of experienced surgeons, bilateral neck exploration for PHP cures 95% of cases. Furthermore, prior to recent advances in imaging technology, the sensitivity of localisation studies was approximately 60–70%.

Given these facts, the National Institutes of Health released guidelines in 1990 for the treatment of PHP that included the recommendation that preoperative localisation was not indicated.

Localisation studies were to be limited to re-operative cases. However, the advent of rapid intraoperative PTH assays and the highly sensitive and specific sestamibi scan (see below) have rekindled interest in preoperative localisation for directed unilateral exploration – the so-called focused approach.

Most patients with PHP have a single adenoma, while entities such as multiple adenoma and four-gland hyperplasia are considerably less frequent.

In a systematic literature review of 20 225 cases of PHP reported, Ruda et al. found that solitary adenomas, multiple gland hyperplasia, double adenomas and parathyroid carcinoma occurred in 88.9%, 5.74%, 4.14% and 0.74% of cases, respectively.

These statistics are consistent across the literature. The fact that the overwhelming majority of patients have unilateral disease or bilateral disease that can be identified by unilateral exploration raises the issue of whether bilateral exploration is mandated in every case. Is it reasonable to expose the patient to the increased morbidity of bilateral exploration to identify the less than 3% of people who will have a second adenoma on the contralateral side? These issues have led many endocrine surgeons to investigate the feasibility of preoperative localisation and directed unilateral exploration. This trend, along with the need to localise pathology in re-operative situations, has spurred the refinement of imaging techniques for parathyroid disease. Table 1.2 provides a summary of the current imaging modalities.