Hyperparathyroidism

Hyperparathyroidism (HPT) refers to increased levels of parathyroid hormone in the body, which often leads to issues with calcium metabolism and phosphate levels. Normocalcaemic hyperparathyroidism refers to high parathyroid hormones levels with a normal calcium level.

🦴 Physiology

Ossification is the process by which bones form. There are 2 mains types of ossification:

1. Endochondrial ossification - this is the most common form and the is the process by which long bones form. It begins with the formation of a cartilaginous model of the bone shape by chondrocytes. This model subsequently becomes ossified by osteoblasts.
2. Intramembranous ossification - this is used in the formation of flat bones such as the skull and sternum. It begins with the differentiation of mesenchymal cells into osteoblasts directly without a cartilaginous model.

The process of ossification begins at weeks 6-7 of embryonic development. This process continues throughout childhood and adolescence as some bones only completely ossify at the age of 25 years old.

Ostebolasts are the secreting cells which secrete collagen which is a major component in bone matrix. They also deposit calcium and phosphate into the bone matrix for bone mineralisation. These minerals then bind to the collagen matrix, initiating the formation of hydroxyapatite crystals. This process is known as calcification, and it solidifies the bone, providing it with the hardness and strength required for its structural functions. Osteocytes, mature bone cells derived from osteoblasts, become embedded in the mineralized bone matrix. They play a role in maintaining bone health and responding to mechanical stresses.

The process of bone mineralization is tightly regulated to maintain mineral homeostasis in the body. Various hormones, such as parathyroid hormone (PTH) and calcitonin, as well as vitamin D, play crucial roles in regulating calcium and phosphate levels in the blood and bone.

Therefore, calcium, phosphate and vitamin D homeostasis is vital for bone formation and bone health:

• Vitamin D
1. 7-dehydrocholesterol is a precursor that is converted to cholecalciferol (vitamin D3) through sunlight exposure. We may also get cholecalciferol through dietary intake.
2. Cholecalciferol is converted into 25-hydroxycholecalciferol (calcidiol) through hydroxylation in the liver.
3. The kidneys then convert calcidiol into 1,25-dihydroxycholecalciferol (calcitriol) through additional hydroxylation with the enzyme 1-α hydroxylase.
4. Calcitriol then serves to increase intestinal calcium and phosphate absorption. It also decreases renal excretion of calcium.

• Parathyroid hormone (PTH)
1. PTH promotes 1-α hydroxylase to produce more calcitriol and increase the serum calcium levels.
2. It encourages calcium and phosphate resorption from the bone by osteoclasts.
3. It decreases renal calcium excretion and increases renal phosphate excretion.
• Calcitonin
1. Calcitonin opposes PTH by inhibiting osteoclast activity and increasing renal calcium excretion to decrease serum calcium levels.
2. Calcitonin not only inhibits bone resorption from osteoclasts but also promotes bone formation by stimulating osteoblasts (although this effect is not as significant as compared to the inhibition of osteoclasts).

On this page we will discuss 3 types of hyperparathyroidism - primary, secondary and tertiary. Although they share their clinical presentation, it is important to discuss how they are caused distinctly, how we investigate them and how we manage them:

Primary hyperparathyroidism (pHPT)

pHPT is a relatively common condition, affecting every 1 in 80 people. It is more common in females than males, with an incidence of 3:1. Most cases occur after the age of 50.

Pathophysiology

In pHPT, there is an autonomous overproduction of PTH leading to hypercalcaemia. This happens because:

• PTH stimulates osteoclastic bone resorption which results in calcium and phosphate release resulting in high calcium and phosphate levels. This is done by stimulating RANKL binding, and IL-1 expression on osteoblasts which all lead to increased osteoclastic activity
• PTH induces calcium reabsorption from urine, as well as decreased calcium excretion, and increased phosphate excretion.
• PTH helps convert inactive vitamin D to active vitamin D (calcitriol), which then enhances calcium reabsorption from the GI tract.

So what are the causes of pHPT?

• Solitary parathyroid adenoma - this is the most common cause (around 85% of cases).
• Multiple parathyroid adenomas - less common (around 4%).
• Parathyroid hyperplasia - this makes up around 15% of cases.
• Parathyroid carcinoma - very rare (around 0.5% of cases).
• Multiple endocrine neoplasia 1 (MEN1) or multiple endocrine neoplasia 2 (MEN2)
• Medications - such as thiazide diuretics or lithium.

🔍 Investigations

• 🥇 Albumin-adjusted serum calcium - this must be taken for individuals with the features indicative of pHPT. Ionised calcium is not recommended when investigating pHPT.

We need to then repeat the test if the result is:

1. ≥2.6mmol/L
2. ≥2.5mmol/L + features of hyperparathyroidism are present

If the albumin-adjusted serum calcium returns as ≥2.6mmol/L or ≥2.5mmol/L with features of pHPT → measure parathyroid hormone.

Seek specialist advice if:

3. PTH is above midpoint of reference range
4. PTH is below midpoint of reference range + albumin-adjusted serum calcium ≥2.6mmol/L

In secondary care, we can investigate further:

• Vitamin D levels - to assess if supplementation is needed.
• Urine calcium excretion - to rule out familial hypocalciuric hypercalcaemia.

After a diagnosis of pHPT is confirmed, we need to:

• Measure eGFR or serum creatinine
• DEXA scan of lumbar spine, distal radius and hip
• Ultrasound scan of renal tract

	Calcium	Phosphate	PTH	ALP
pHPT	High		High/normal	High

💡

Familial hypocalciuric hypocalcaemia (FHH):

This is an autosomal dominant condition characterised by hypercalcemia and low levels of calcium excretion in the urine (hypocalciuria). PTH levels are normal or slightly raised and urinary calcium is low. FHH is caused by loss-of-function mutations in the gene on the long arm of chromosome 3 encoding for the calcium-ion-sensing G-protein-coupled receptor in the kidney and parathyroid gland

🧰 Management

• Manage the hypercalcaemia
• Vitamin D supplementation - for example, using ergocalciferol. This is beneficial pre-operatively if deficiency is noted.
• Bisphosphonates - considered if the patient is at risk of a fracture.

Surgical management:

• Surgery is indicated there is:
1. Symptoms of hypercalcaemia (thirst, polyuria, or constipation)
2. End-organ disease (renal stones, fragility fractures or osteoporosis)
3. Albumin-adjusted serum calcium ≥2.

Prior to surgery we need to do preoperative imaging:

• 🥇 Ultrasound - usually first-line option for preoperative imaging.
• 🥈 Sestamibi scan - an alternative option for parathyroid imaging. It is a form of nuclear medicine using technetium-99m.

The options for surgery then depend on the imaging findings:

• Single adenoma - 4-gland exploration or focused parathyroidectomy
• Hyperplasia of all 4 glands - total parathyroidectomy
• Parathyroid carcinoma - tumour resection

Post-operative follow-up then includes:

1. Measure albumin-adjust serum calcium - measured prior to discharge (for baseline) then measured again at 3-6 months to determine if the surgery was successful. It is then monitored annually afterwards.
2. DEXA scan - every 2-3 years.
3. Renal tract ultrasound - at diagnosis and when suspecting a renal stone.

Non-surgical management:

If surgery is declined, the patient should be offered monitoring and cinacalcet (a calcimimetic) if albumin-adjusted serum calcium is:

• ≥2.85mmol/L + symptoms of pHPT
• ≥3.0mmol/L

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Click to view the NICE pathway for management of pHPT:

Secondary hyperparathyroidism (sHPT)

In sHPT, there is overproduction of PTH due to hypocalcaemia or hyperphosphataemia as chronic levels lead to reactive hyperplasia of sHPT.

Pathophysiology

In sHPT, low calcium levels or high phosphate lead to reactive hyperplasia of the parathyroid glands. This leads to increased PTH secretion to try and correct calcium and phosphate levels.

What causes these derangements in calcium and phosphate levels?

• Chronic kidney disease (CKD) - this is the most common cause. This leads to impaired renal phosphate excretion and hyperphosphataemia which results in increased PTH secretion. CKD also leads to decreased activation of vitamin D and decreased intestinal calcium resorption and decreased renal calcium reabsorption. This leads to hypocalcaemia and elevated levels of PTH secretion.
• Renal osteodystrophy (CKD mineral bone disease)

🔍 Investigations

• PTH - elevated.
• Calcium - normal or decreased.
• Phosphate - normal or elevated.
• ALP - elevated.
• U&Es and eGFR - to assess renal function.

🧰 Management

• Manage underlying condition
• Vitamin D supplementation - with ergocalciferol for example.
• Calcium supplementation - with calcium carbonate for example.
• Dietary phosphate restriction and phosphate binders (such as sevelamer or calcium acetate)

Tertiary hyperparathyroidism (tHPT)

Tertiary HPT occurs due to prolonged, untreated secondary HPT.

Pathophysiology

Hyperplasia of the parathyroid glands occurs due to increased activity of the parathyroid glands in sHPT. This results in chronic overproduction of PTH despite treatment of the underlying cause of the HPT. This will lead to inappropriately high levels of calcium absorption from the intestines, reabsorption from kidneys and resorption from bones → hypercalcaemia.

🔍 Investigations

• PTH - markedly elevated.
• Calcium - elevated.
• Phosphate - elevated.
• ALP - elevated.
• U&Es and eGFR - to assess renal function.

🧰 Management

Same as sHPT, but it will involve managing hypercalcaemia instead of hypocalcaemia. This may be done with cinacalcet which normalises the calcium levels.

😷 Presentation

The majority of patients with HPT are asymptomatic.

When patients do present with symptoms, it results in the following features:

• Hypercalcaemia features:

Remember that hypercalcaemia causes: “stones, bones, abdominal groans, moans, thrones and psychic overtones”.

1. Stones: 
• Renal stones (nephrolithiasis) causing pain, and nephrocalcinosis (Albright calcinosis) which is the deposition of calcium oxalate/calcium phosphate in the kidneys.
2. Bones:
• Bone related complications like bone pain, arthralgia, myalgia.
• Hypercalcaemia can lead to osteoporosis, osteomalacia, arthritis and pathological fractures.
3. Abdominal groans:
• Gastrointestinal symptoms like pain, nausea, vomiting and constipation.
• Hypercalcaemia can lead to peptic ulcer disease and acute pancreatitis.
4. Moans: 
• Fatigue and malaise.
5. Thrones (sitting on the toilet - referring to the toilet as a throne):
• Polyuria, polydipsia (sitting on the toilet as you are sitting on a throne), because hypercalcaemia impairs urine concentration that is refractory to ADH administration → nephrogenic diabetes insipidus.
6. Psychic overtones: 
• Lethargy, confusion, depression and memory loss.
• Cardiovascular effects:
• Left ventricular hypertrophy - due to the deposition of calcium salts in the heart.
• Short QTc interval
• Hypertension - mechanism is not fully understood, but presumed to be due to direct vasoconstriction and renal failure. It's also contributed to by the deposition of salts in the arteries which reduces arterial flexibility.
💡

Familial hypocalciuric hypocalcaemia (FHH):

This is an autosomal dominant condition characterised by hypercalcemia and low levels of calcium excretion in the urine (hypocalciuria). PTH levels are normal or slightly raised and urinary calcium is low. FHH is caused by loss-of-function mutations in the gene on the long arm of chromosome 3 encoding for the calcium-ion-sensing G-protein-coupled receptor in the kidney and parathyroid gland

Summary