3rd April 2024

Parathyroid Conditions

The Parathyroid Gland

Background

The four parathyroid endocrine glands are located close to, but functionally separate from, the thyroid gland. Given their location, they are at risk of damage during neck dissection or thyroidectomy. Parathyroid hormone (PTH) secreted by the parathyroid gland, regulates serum calcium and phosphate levels and is involved in bone metabolism. 

Hyperparathyroidism

This occurs when there is excessive PTH secretion from the parathyroid glands. The aetiology can be primary, secondary or tertiary. Most patients with primary hyperparathyroidism are asymptomatic and the condition is detected on routine laboratory screening. Other patients may present with clinical and biochemical abnormalities related to hypercalcaemia, such as renal stones and pancreatitis.  

Clinical manifestations are non-specific with fatigue, myalgia, anxiety, and poor sleep the most common. Gastrointestinal symptoms such as constipation and nausea occur less frequently. The classical triad in MCQs is a patient with polyuria, polydipsia, and bony pain. A consequence of extremely high levels of PTH is abnormal bone turnover and/or mineralisation, which increases the risk of developing fragility fractures.

Aetiology

Primary hyperparathyroidism occurs when there is autonomous overproduction of PTH. It is a common condition, predominantly affecting older and post-menopausal women. Most cases (80%) are caused by a single parathyroid adenoma, with multiple gland hyperplasia responsible for the remaining 10-20%. Parathyroid carcinoma occurs in around 1% of cases. Inherited conditions such as multiple endocrine neoplasia (MEN) 1 and 2 can predispose to gland hyper-productivity, with hyperparathyroidism the presenting feature of 90% of patients with MEN1. 

Secondary hyperparathyroidism is the result of increased PTH production in response to hypocalcaemia. Commonly due to chronic kidney disease (eGFR ≤ 45 ml/min/1.73m2) or vitamin D deficiency, hypocalcaemia, combined with calcitriol deficiency and phosphate retention, leads to a compensatory rise in parathyroid hormone to maintain homeostasis. In patients with end-stage renal failure (ESRF), hypocalcaemia commonly occurs due to 1a-hydroxylase deficiency, a renal enzyme responsible for the conversion of 25-hydroxyvitamin D to the active form 1,25-dihydroxyvitamin D (calcitriol). 

Tertiary hyperparathyroidism occurs when there is parathyroid gland hyperplasia due to chronic hypocalcaemia.

Untreated chronic hypocalcaemia in patients with advanced or dialysis-dependent kidney failure can lead to autonomous PTH secretion, irrespective of calcium concentrations, caused by gland hyperplasia.

Diagnostics

Diagnosis is by blood sampling looking at calcium, phosphate, parathyroid hormone, alkaline phosphatase and vitamin D levels. Other causes of hypercalcaemia, such as familial hypocalciuric hypercalcaemia, should be excluded. Table 1 shows the typical biochemical findings in primary, secondary and tertiary hyperparathyroidism. Whilst imaging is not necessary for diagnosis, CT neck or cervical ultrasonography may be useful for planning surgery and identifying concomitant thyroid disease. 

Table 1: Typical biochemistry in primary, secondary and tertiary hyperparathyroidism

Management

Curative treatment centres around elective parathyroidectomy, with pre-operative vitamin D repletion advised if deficient. Successful kidney transplantation removes the driving force for tertiary hyperparathyroidism and leads to spontaneous resolution in around 60% of patients after 2 years.

In patients with resistant hypercalcaemia, second line treatments such as intravenous bisphosphonates may be given, with an onset of action in 2-4 days; or denosumab, calcitonin or calcimimetics such as cinacalcet. Cinacalcet increases the sensitivity of calcium receptors on the parathyroid gland to serum calcium and thus reduces PTH secretion, with particular use in secondary hyperparathyroidism.

Emergency treatment centres around symptomatic management of hypercalcaemia and treatment of the underlying cause. Restoration of circulating volume via aggressive rehydration, occasionally requiring up to 10 litres of fluid in the first 24 hours, is key to emergency management. Patients with hypercalcaemia-induced renal failure may require dialysis.

Hypoparathyroidism

This is characterised by hypocalcaemia, hyperphosphatemia and low/inappropriately normal levels of PTH. In pseudohypoparathyroidism, the findings are similar but PTH is raised due to resistance. Some patients remain asymptomatic with low serum calcium levels. Symptoms related to hypocalcaemia include:

• Tetany: muscle twitches, cramps, or spasms
• Perioral, hand and feet paraesthesia
• Altered mental state 
• Generalised seizures: may indicate acute or severe hypocalcaemia
• Trousseau’s sign: painful clasping of fingers and hands when blood pressure cuff is inflated
• Chvostek’s sign: tapping the facial nerve in front of the ear elicits ipsilateral facial muscle contraction

Aetiology

Primary hypoparathyroidism is a result of relative or absolute PTH deficiency and occurs most commonly post-neck surgery. Rare causes include infiltrative or destructive diseases such as tumours, autoimmune destruction, heavy metal deposition (iron/copper), or genetic syndromes such as Di George syndrome.

Pseudohypoparathyroidism occurs due to defective PTH receptors or resistance to PTH. It is an autosomal dominant condition characteristically associated with a short stature, round face, dental hypoplasia and short 4th and 5th metacarpals. PTH levels are intact or highly elevated, distinguishing it from primary hypoparathyroidism. 

In pseudopseudohypoparathyroidism patients have the characteristic phenotype of pseudohypoparathyroidism (known as Albright’s hereditary osteodystrophy) with normal biochemistry.

Diagnostics

Diagnosis requires confirmed hypocalcaemia with low levels of PTH and the absence of hypomagnesaemia. Reversible causes of hypoparathyroidism include hypomagnesaemia, iron or copper overload. Investigations for specific causes of hypoparathyroidism, as mentioned above, may be considered. Table 2 shows the typical biochemical findings in primary, pseudohypoparathyroidism and pseudopseudohypoparathyroidism. 

Table 2: Typical biochemistry findings in hypoparathyroidism

Management

Acute, symptomatic hypocalcaemia is a medical emergency, therefore immediate intravenous replacement with close ECG monitoring is crucial as severe hypocalcaemia can cause prolonged QT interval and tachyarrhythmias.  Investigation for and treatment of hypomagnesemia (which may exacerbate hypocalcaemia) should also be commenced.

In patients with minimal symptoms, oral supplementation and ensuring vitamin D stores are replete, may be suitable. The signalling defect in pseudohypoparathyroidism is incurable, therefore maintenance of normal calcium and phosphate through supplementation is key. 

Patients undergoing neck surgery with a risk of parathyroid gland interference should have serum calcium levels checked immediately postoperatively and prior to discharge, with initial supplementation recommended.

Paraneoplastic syndromes affecting the parathyroid gland

Hypercalcaemia occurs in approximately one-quarter of patients with cancer. Of these patients, the majority (80%) are caused by secretion of parathyroid hormone-related peptide (PTHrP), which leads to hypercalcemia via osteoclastic bone resorption. PTHrP is not detected on classical assays and thus, patients present with suppressed PTH (distinguishing patients from those with primary hyperparathyroidism). 

References

• Mannstadt, M. (2021) Parathyroid hormone secretion and action. UpToDate.  https://www.uptodate.com/contents/parathyroid-hormone-secretion-and-action
• BMJ Best Practice (2021). Primary hyperparathyroidism. BMJ Best Practice. https://bestpractice.bmj.com/topics/en-gb/133
• Shoback, D., Duh, Q. (2018) Hypoparathyroidism. BMJ Best Practice.
  https://bestpractice.bmj.com/topics/en-gb/132
• Horwitz, M. (2020) Hypercalcaemia of malignancy: Mechanisms. UpToDate. https://www.uptodate.com/contents/hypercalcemia-of-malignancy-mechanisms

Calcium Metabolism

Background 

Highly sensitive calcium-sensing receptors (CaSR) on the parathyroid glands are responsible for detecting any changes in calcium concentration and regulating secretion of PTH. Together with calcitriol (1,25-dihydroxyvitamin D) and fibroblast growth factor 23 (FGF23), PTH regulates calcium and phosphate homeostasis. PTH acts to counter detected hypocalcaemia via three mechanisms:

• Increased bone resorption: targets osteoblasts and osteocytes, particularly in cortical bone, to enhance bone remodelling
• Decreased urinary calcium excretion: PTH increases calcium reabsorption in the distal tubule, as well as inhibiting proximal tubular reabsorption of phosphate
• Increased intestinal calcium and phosphate absorption: mediated by increased activated vitamin D

Vitamin D Metabolism 

In response to reduced extracellular calcium, PTH increases the activity of the renal enzyme responsible for hydroxylation (1-alpha-hydroxylase) and, thus, activation of calcidiol to calcitriol. Activated vitamin D (1,25-dihydroxyvitamin D) increases intestinal calcium absorption and osteoclastic bone resorption. Under normal physiological conditions, calcitriol acts via a negative feedback loop to decrease PTH production.

Vitamin D deficiency

This is the most common nutritional deficiency worldwide. Vitamin D may be ingested from certain plant products (as ergocalciferol), with subsequent hepatic and renal hydroxylation, or as cholecalciferol from animal products such as fish and eggs or by endogenous synthesis in the skin when exposed to sunlight. Therefore, deficiency may arise due to reduced intake or intestinal absorption, reduced sun exposure, or decreased endogenous synthesis. 

Persistent vitamin D deficiency may result in osteomalacia, with patients commonly presenting with percussion tenderness, bony pain and proximal muscle weakness, which may combine to cause a waddling gait. Such individuals are at an increased risk of fragility fractures. Resultant hypocalcaemia leads to a compensatory rise in PTH.

Management 

Regular vitamin D supplementation of 600-800 IU per day is recommended to prevent deficiency in at-risk patients. National consensus guidelines recommend 50,000 IU vitamin D2 or vitamin D3 once weekly for 7 weeks, with those with malabsorption syndromes or other comorbidities utilising a higher dose regimen.

Hypocalcaemia

This is defined as calcium levels <2.20mmol/mol in the presence of normal serum plasma protein concentrations. It is crucial to check serum albumin levels and adjust accordingly, as over 40% of circulating calcium is bound to albumin. 

Both the absolute level and rate of the fall in adjusted serum calcium levels are important, with symptoms typically developing if AdjCa ≤1.9mmol/L or if there is a rapid decrease. 

Measuring PTH level is crucial to identifying the cause of hypocalcaemia. Causes of hypocalcaemia with a low PTH have been previously described in the hypoparathyroidism section.  Causes of hypocalcaemia with high PTH include:

• Vitamin D deficiency/chronic kidney disease: resulting in secondary hyperparathyroidism
• Pseudohypoparathyroidism, where impaired PTH response results in renal calcium excretion  
• Acute pancreatitis: hypocalcaemia due to calcium saponification 
• Sepsis and severe burns: multifactorial causes of hypocalcaemia

Complications

Severe or symptomatic hypocalcaemia may result in life-threatening complications. It characteristically causes prolonged QT interval, which can lead to life-threatening dysrhythmias such as torsades de pointes and ventricular fibrillation. 

Management

Treatment of severe or symptomatic hypocalcaemia is a medical emergency, managed with 10% calcium gluconate, with repeated doses given until a patient is asymptomatic, or calcium level has normalised. Chronic, or mild/asymptomatic hypocalcaemia can be managed with oral calcium and vitamin D supplements.

Care must be exercised as overzealous calcium replacement, particularly when given via the intravenous route, can also lead to serious arrhythmias.

Hypercalcaemia

Severe hypercalcaemia is defined as >3.5mmol/L. Patients may tolerate high calcium levels if there has been a slow increase, however more rapid rises, despite the overall level, often result in a patient being symptomatic. Malignancy-related hypercalcaemia often rises more rapidly, resulting in patients becoming highly symptomatic.

Rarely, patients with ESRF who develop hypercalcaemia, hyperphosphatemia or hyperparathyroidism may present with skin ischaemia and necrosis. This complication, known as calciphylaxis, is due to arteriolar calcification, resulting in microvascular occlusion.

Acute hypercalcaemia also directly shortens the QT interval.

Causes

Hypercalcaemia is caused by either primary hyperparathyroidism or cancer in over 90% of cases. Malignancy-related hypercalcaemia occurs more commonly in patients with multiple myeloma, leukaemia, lung or breast cancers and may be due to PTHrP secretion or bony metastases. Other causes include:

• Excessive vitamin D or calcium supplementation 
• Thyrotoxicosis : due to rapid bone turnover
• Sarcoidosis: increased vitamin D activation by macrophages
• Hypercalcaemia of immobility: commonly in young patients who develop massive bone demineralisation following prolonged immobility 
• Familial hypocalciuric hypercalcaemia: autosomal dominant cause of mild hypercalcaemia and hypocalciuria

Management 

Emergency treatment is discussed above (see The Parathyroid Gland: Hyperparathyroidism).

If there is poor response to initial rehydration, intravenous bisphosphonates may be used, which inhibit osteoclastic bone resorption, but have a more delayed onset of action.

Glucocorticoids may be beneficial in the management of calcitriol-induced hypercalcaemia secondary to sarcoidosis, tuberculosis, and lymphomas. Cinacalcet increases the sensitivity of CaSRs on the parathyroid gland to calcium, thus are useful in patients with secondary hyperparathyroidism.

References

• UpToDate. Parathyroid hormone secretion and action. https://www.uptodate.com/contents/parathyroid-hormone-secretion-and-action
• BMJ Best Practice. (2021) Assessment of hypocalcaemia. BMJ Best Practice. https://bestpractice.bmj.com/topics/en-gb/160/urgent-considerations
• Goltzman, D. (2021). Treatment of hypocalcaemia. UpToDate. https://www.uptodate.com/contents/treatment-of-hypocalcemia#H596754

Genetic conditions affecting parathyroid glands

MEN syndromes

Multiple endocrine neoplasia (MEN) syndromes are a rare group of disorders characterised by an inherited predisposition to benign or malignant neoplasms of the endocrine system with characteristic organ involvement.

Pathophysiology 

MEN syndromes are a group of autosomal dominant disorders divided into ‘types’ by clinical characteristics. MEN1 affects 1-3 in 100,000 and is due to a defect in the MEN1 gene, whilst MEN2 has been reported in approximately 1000 families worldwide and is caused by a mutated RET proto-oncogene. Based on clinical characteristics, MEN2 can be further subdivided into MEN2A and MEN2B subtypes (see Table 1). Other genetic conditions affecting the parathyroid gland include pseudohypoparathyroidism. 

Table 1: characteristics of different MEN syndromes. 

*This is the most common presenting feature of individuals with MEN1.

Tumours form in distinctive organ systems and may be functioning or non-functioning; hypersecretion of hormones from functioning tumours leads to specific symptoms dependent on tumour type. Individuals with MEN1 can present with hypercalcaemia caused by hyperparathyroidism. 40-70% of patients with MEN1 have pancreatic neuroendocrine tumours; ranging from insulinomas, which present with hypoglycaemia, VIPomas causing severe, watery diarrhoea, to gastrinomas, (Zollinger-Ellison syndrome). Zollinger-Ellison syndrome is the most common cause of symptomatic disease in patients with pancreatic tumours.

Management

Early prophylactic thyroidectomy in patients diagnosed genetically with MEN2 in childhood may be indicated, given that most patients will ultimately develop MTC. Otherwise, treatment centres around surgical management of tumours and medical management of symptomatology. Routine monitoring of known carriers begins in childhood and should take place every few years to reduce associated morbidity and mortality.

DiGeorge syndrome

Di George syndrome is an autosomal dominant syndrome caused by a deletion in chromosome 22 (22q11.2). Nearly two-thirds of children with Di George syndrome present with hypocalcaemia in the neonatal period, characterised by jitteriness, tetany, or seizures. This is caused by underdevelopment of the parathyroid glands. Patients may also be identified during the neonatal period due to congenital heart defects, such as tetralogy of Fallot, atrial or ventricular septal defects or truncus arteriosus. Children classically present with a triad of cardiac anomalies, hypoplastic thymus and hypocalcaemia.

However, some children do not present with such overt symptoms and, therefore, may be diagnosed later in life due to delayed development, failure to thrive or frequent infections. An absent or hypoplastic thymus gland, resulting in T cell deficiency, may lead to recurrent sinopulmonary infections or viral infections. Developmental delay occurs in most patients with DGS, with many children experiencing speech delay, in part due to palatal abnormalities such as cleft palates.

Investigations

Di George syndrome is diagnosed based on reduced CD3+ T cells, together with characteristic clinical findings (as described above) or detected deletion of chromosome 22q11.2.

Management 

Acute management in neonates centres around management of hypocalcaemia and surgical correction of significant congenital cardiac defects. Feeding and swallowing problems due to palatal or gastrointestinal defects may be critical issues in the first few days of life. Those with complete athymia are unlikely to survive beyond the first few years of life. 

Autoimmune polyendocrinopathy syndrome

Type 1 autoimmune polyendocrinopathy syndrome, also known as ‘autoimmune polyglandular syndrome’, is a rare autosomal recessive condition associated with autoimmune adrenalitis (Addison’s disease), chronic mucocutaneous candidiasis and primary hypoparathyroidism. There is an increased prevalence amongst people from Finland, Sardinia and Iranian Jews. 

Type 2 autoimmune polyendocrinopathy syndrome, also known as Schmidt’s disease, is more prevalent and has several modes of inheritance, including autosomal recessive, polygenic and autosomal dominant. This syndrome encompasses Addison’s disease, autoimmune thyroid disease, and Type 1 diabetes mellitus. Adrenal insufficiency is the initial presentation in around 50% of patients.

References 

• Gorrigan, R., Druce, M. (2021) Multiple endocrine neoplasia syndromes.  BMJ Best Practice. https://bestpractice.bmj.com/topics/en-gb/866
• Lips, C. (2021) Approach to therapy in multiple endocrine neoplasia type 2. UpToDate [Online] https://www.uptodate.com/contents/approach-to-therapy-in-multiple-endocrine-neoplasia-type-2
• National Organisation for Rare Disorders (NORD). Autoimmune Polyglandular Syndrome Type 1. Rare Disease Database [Online] https://rarediseases.org/rare-diseases/autoimmune-polyglandular-syndrome-type-1/
• BMJ Best Practice (2020) DiGeorge Syndrome. BMJ Best Practice [Online] https://bestpractice.bmj.com/topics/en-gb/947