Hyperparathyroidism

Description

Hyperparathyroidism is a clinical condition characterised by hypercalcemia resulting from an excessive secretion of parathyroid hormone (PTH). The condition can be primary, secondary, or tertiary based on the underlying cause.

Pathogenesis

The parathyroid glands, located posterior to the thyroid gland, are responsible for producing PTH. This hormone plays a key role in regulating serum calcium levels. PTH achieves this by acting on various sites:

• Bone: PTH stimulates osteoclast activity, leading to bone resorption and the release of calcium and phosphate into the bloodstream.
• Kidneys: PTH increases the reabsorption of calcium in the renal tubules, while inhibiting the reabsorption of phosphate. This leads to increased calcium levels in the blood and phosphate excretion in urine.
• Intestines: PTH indirectly increases calcium absorption from the intestine by stimulating the kidneys to convert 25-hydroxyvitamin D to its active form, 1,25-dihydroxyvitamin D. This active form of vitamin D enhances the absorption of dietary calcium and phosphate in the intestine.

In the setting of primary hyperparathyroidism, there is an autonomous overproduction of PTH, most commonly due to a parathyroid adenoma. This leads to hypercalcaemia due to increased calcium resorption from bone and increased calcium reabsorption in the kidneys.

Secondary hyperparathyroidism, on the other hand, is a physiological response to hypocalcaemia, often due to chronic kidney disease or vitamin D deficiency. The low calcium levels stimulate the parathyroid glands to produce more PTH in an attempt to increase serum calcium levels.

Tertiary hyperparathyroidism is typically a sequel of longstanding secondary hyperparathyroidism, particularly in the context of renal disease. Over time, the parathyroid glands become hyperplastic and secrete PTH autonomously, leading to hypercalcaemia.

In each form of hyperparathyroidism, the dysregulated PTH secretion disrupts calcium homeostasis, leading to a range of clinical features and complications, such as nephrolithiasis, bone disease, and neurocognitive symptoms.

Subtypes

• Primary Hyperparathyroidism: Caused by an autonomous overproduction of PTH by the parathyroid glands, typically due to a parathyroid adenoma (85% of cases), hyperplasia of all parathyroid glands (15% of cases), or less commonly, a parathyroid carcinoma (<1% of cases).
• Secondary Hyperparathyroidism: Occurs as a physiological response to hypocalcemia and/or vitamin D deficiency, often due to chronic kidney disease. The low calcium levels stimulate all four parathyroid glands to secrete PTH.
• Tertiary Hyperparathyroidism: Develops following long-standing secondary hyperparathyroidism, particularly in the setting of renal disease. Over time, the chronically stimulated parathyroid glands become autonomous, leading to hypercalcemia.

Epidemiology, Risk Factors & Associations

• Primary Hyperparathyroidism: Predominantly affects post-menopausal women (F:M ratio of 3:1). The estimated prevalence in the general population is 0.1-0.4%.
• Secondary Hyperparathyroidism: Commonly associated with chronic kidney disease (CKD). The prevalence increases with the severity of CKD, affecting nearly 100% of patients on dialysis.
• Tertiary Hyperparathyroidism: Predominantly seen in patients with a long history of secondary hyperparathyroidism, particularly those with renal disease on long-term dialysis.

Clinical Features

The clinical manifestations of hyperparathyroidism can be varied and are commonly encapsulated in the phrase “bones, stones, abdominal groans, and psychic moans.”

• Bones (osteitis fibrosa cystica): Over time, high levels of PTH can lead to bone resorption, causing bone pain and increased risk of fractures. Approximately 15-20% of patients with primary hyperparathyroidism present with bone-related symptoms.
• Stones (renal calculi): Hypercalcemia promotes the formation of kidney stones, and this is seen in about 20% of patients with primary hyperparathyroidism.
• Abdominal groans (gastrointestinal symptoms): High calcium levels can lead to peptic ulcers and pancreatitis due to increased gastric acid secretion. Constipation, nausea, and loss of appetite are also common.
• Psychiatric moans (psychiatric symptoms): Patients can present with changes in mood and cognition, including depression, fatigue, and memory loss.

Other common clinical features include polyuria and polydipsia due to the effect of high calcium levels on kidney function. Hypertension is seen in approximately 30% of patients with primary hyperparathyroidism. However, a significant number of patients with primary hyperparathyroidism, estimated at 25-30%, are asymptomatic at the time of diagnosis, and the condition is discovered during routine blood tests.

In secondary hyperparathyroidism, symptoms are often related to the underlying cause of the condition (for example, symptoms of renal disease). In tertiary hyperparathyroidism, symptoms are similar to those of primary hyperparathyroidism, but can be more severe due to longstanding disease.

Complications

Chronic hyperparathyroidism can lead to hypercalcemic crisis, renal stones, nephrocalcinosis, osteoporosis, peptic ulcers, and pancreatitis.

Pathological Features

Histopathology

• Primary: Adenomas appear as well-circumscribed, encapsulated nodules with chief cell hyperplasia. Carcinomas are larger with invasive features and cellular atypia.
• Secondary and Tertiary: Parathyroid hyperplasia involves all four glands and is characterised by chief cell hyperplasia.
• Brown tumours – Histologically identical to giant cell tumour. The term “brown” tumour comes from colour imparted by haemorrhage

Biochemistry

• Primary: Elevated calcium, elevated or inappropriately normal PTH, decreased phosphate.
• Secondary: Low or normal calcium, elevated PTH, high phosphate (unless renal disease).
• Tertiary: Elevated calcium and PTH, variable phosphate levels.

Radiological Features

General Features

The features of hyperparathyroidism can be seen in multiple systems, including the skeletal, renal, and gastrointestinal systems.

Skeletal System

• Subperiosteal bone resorption, particularly along the radial aspect of the middle phalanges of the index and middle fingers
• Terminal tuft erosion
• Distal clavicle resorption
• Brown tumours (osteitis fibrosa cystica) – Lytic (cystic), expansile lesion with geographic non-sclerotic margins and no matrix production, cortical destruction, periosteal reaction or soft tissue mass.
• Salt-and-pepper skull (granular appearance of the diploic space in the skull)
• Rugger-jersey spine (alternating sclerotic and lucent bands seen at the vertebral body endplates) are classic but less commonly seen findings.
• Metastatic soft tissue calcification (more common in secondary hyperparathyroidism)
• Chondrocalcinosis

Renal System

• Nephrocalcinosis and renal calculi. On ultrasound, kidneys can appear echogenic due to calcium deposits. CT is the most sensitive and specific imaging modality for detecting renal stones, which can be seen as high-attenuation objects within the renal calyces or ureters.

Gastrointestinal System

• Peptic ulcers and pancreatitis.

Parathyroid Glands

• US: Hyperplastic or adenomatous parathyroid glands can be identified on ultrasound as hypoechoic or isoechoic nodules posterior to the thyroid lobes.
• CT: Can identify ectopic parathyroid tissue. On contrast-enhanced CT, parathyroid adenomas typically enhance rapidly and washout quickly.
• MRI: Adenomas typically showing low signal intensity on T1-weighted images and high signal intensity on T2-weighted images. Post-contrast, they typically demonstrate strong enhancement.
• NM: Sestamibi scintigraphy, are frequently used for the detection of parathyroid adenomas or hyperplasia, with the radionuclide concentrating in the overactive parathyroid tissue.

XR

• Hand: Feathery subperiosteal resorption particularly along the radial aspect, cortical tunnelling, acro-osteolysis and brown tumours
• Skull: Salt and pepper (pepper-pot) skull, brown tumours
• Spine: Rugger jersey spine.

US

• Hypoechoic or isoechoic nodules posterior to the thyroid lobes
• Echogenic kidneys in case of nephrocalcinosis.

CT

• Parathyroid adenomas or hyperplasia may show rapid enhancement and washout on contrast-enhanced studies
• High-attenuation renal calculi
• Features of pancreatitis.

MRI

• Parathyroid adenomas typically show low signal intensity on T1-weighted images and high signal intensity on T2-weighted images.
• Post-contrast, they typically demonstrate strong enhancement.

NM

• Sestamibi scintigraphy: Concentration of radionuclide in the overactive parathyroid tissue.

Grading and Staging

No specific staging system exists for hyperparathyroidism. Severity is typically determined based on calcium and PTH levels, renal function, and the presence of complications.

Diagnosis

The diagnosis of hyperparathyroidism is typically made by demonstrating hypercalcaemia along with an inappropriately elevated or normal PTH level.

Differential Diagnosis

• Familial hypocalciuric hypercalcaemia
• Malignancy-associated hypercalcaemia
• Thiazide-induced hypercalcaemia
• Lithium-induced hypercalcaemia

Imaging-based

• Differentials for rugger jersey spine:
  • Osteopetrosis – sandwich vertebra
  • Paget’s disease of the bone – picture frame vertebra

Management

• Primary: Parathyroidectomy is the treatment of choice. Medical management with cinacalcet or bisphosphonates may be used when surgery is not possible.
• Secondary: Managed by treating the underlying cause, vitamin D replacement, phosphate binders, and limiting dietary phosphate intake.
• Tertiary: Usually requires parathyroidectomy due to autonomous gland function.