Signs and Symptoms of Hyperparathyroidism

Calcium is required in the body for a number of cellular and extra-cellular functions.  Thus, it is not surprising that the disturbance of calcium homeostasis associated with primary hyperparathyroidism may lead to a wide range of signs and symptoms. The “bones, stones, moans, and groans” mnemonic recited by medical trainees year after year has served as a reminder of the multisystem implications of this disease.  The presentation of primary hyperparathyroidism has also changed over time.  The main contributing factor to this is likely the availability of serum measurement of calcium, and subsequently parathyroid hormone (PTH).  In countries in which these tests are readily available, striking clinical presentations of advanced bone disease and severe kidney manifestations are now rare.  Currently, most patients present with asymptomatic hypercalcemia discovered on routine biochemical screening. 

Hypercalcemic Crisis

Hypercalcemic crisis is an uncommon presentation in primary hyperparathyroidism.  This clinical entity is characterized by a significant elevation in serum calcium (often >14mg/dL) associated with a decreased level of consciousness and potentially life threatening deterioration in cardiovascular, gastrointestinal, and renal function.  These patients require admission to hospital for prompt intravenous volume expansion and medications (may include diuretics, bisphosphonates and others) to reduce serum calcium levels followed by surgical parathyroidectomy. 

Bones

PTH raises the serum calcium level partly by increasing osteoclast mediated bone resorption.  With prolonged elevation, this can result in a decline in bone mineral density, osteoporosis, and increased fracture risk.  An extreme form of parathyroid bone disease termed osteitis fibrosa cystica is characterised by significant loss of bone density, development of bone cysts and brown tumors, skeletal deformity, bone pain, and a propensity for pathologic fractures.  Fortunately, it is quite rare, particularly in developed countries where serum calcium and PTH measurement are readily available.  All patients with primary hyperparathyroidism should undergo a determination of bone mineral density via dual-energy x-ray absorptiometry (DEXA) to: 1) determine the extent of bone loss; 2) follow for worsening disease in patients undergoing observation; and 3) monitor improvement post-surgery.  Loss of bone mineral density associated with hyperparathyroidism may disproportionately affect the distal radius, so a 3-site study (hip, spine and distal radius) is typically ordered.  Following parathyroidectomy, bone mineral density may increase by 8–12%.  This improvement appears to be durable even a decade after surgery.

Kidneys

Patients with hyperparathyroidism may develop kidney stones or nephrocalcinosis (deposition of calcium salts in the renal parenchyma).  Over time, the renal effects may result in a decline in renal function.    In some patients, the diagnosis of hyperparathyroidism is a direct result of a work-up in those initially presenting with calcium-containing stones.  Symptomatic kidney stones are seen in a small proportion of patients (<10-20%) with primary hyperparathyroidism.  However, silent stones seen on imaging may be present in some patients.  The development of stones is thought to be related to hypercalcuria; however, the level of calcium in the urine alone has not been shown to be an accurate predictor of future kidney stones.  Patients that have kidney stones at presentation are likely to develop further stones with observation.  Surgery is effective in reducing the risk of future stones.

Neurocognitive/Psychiatric Symptoms

Hyperparathyroidism is associated with a wide array of symptoms related to neurocognitive and psychiatric function.  Patients often report difficulties with memory and concentration.  They may describe a feeling of brain fog that impairs their ability to focus on tasks.  Patients may also report mood related problems including depression, anxiety and irritability.  Rarely, there may be more severe symptoms including hallucinations, delusions, and paranoid ideation.  Patients may also report weakness, general fatigue, and sleep disturbance.  Joint and muscle pain may also be a prominent symptom in some patients.  While the specific etiology of these symptoms is not clearly defined, they have been noted with increased frequency in this population.  In addition, patients not uncommonly report improvements in these symptoms following surgery.  While many patients may benefit, it is difficult to predict which patients will see improvements in which symptoms.  As a result, the International Working Group on Asymptomatic Primary Hyperparathyroidism does not characterize these symptoms as a definitive indication for surgery.  Surgeons should have a detailed discussion about these symptoms and their response to surgery when planning treatment. 

The symptoms mentioned in the preceding paragraph may result in a reduction in quality of life observed in this patient group.  Both general and disease specific measures have been used.  The Parathyroidectomy Assessment of Symptoms (PAS) score is a disease specific tool evaluating quality of life on 13 disease-specific items.  It is correlated with more general scales such as the SF-36.  Using these tools, studies have been able to demonstrate an improvement in quality of life following parathyroid surgery.  As many as 80-95% of patients will report some improvement of these symptoms following parathyroidectomy.  Disturbances of mood and muscle pain are often positively impacted.  Given the vague nature and potentially gradual onset, some patients do not realize they suffer from these symptoms until they experience an improvement post-operatively.  Research also suggests that improvements in these symptoms may be durable over long-term followup.

Cardiovascular

Primary hyperparathyroidism may have an adverse impact on cardiovascular function.  Higher rates of hypertension, arrhythmias, left ventricular hypertrophy/dysfunction, and coronary artery disease have been observed.  Proposed mechanisms for these observations include direct effects of hypercalcemia, high PTH levels, and vitamin D deficiency, as well as PTH-mediated activation of the renin-angiotensin-aldosterone system.  Patients with hyperparathyroidism also have increased all-cause and cardiovascular mortality when compared to the general population.  Currently, the impact of parathyroidectomy on cardiovascular events and mortality is not well-defined, but some research has suggested a benefit may exist.