Hyperparathyroidism

• Can be primary which represents autonomous, spontaneous over production of PTH or secondary. It can also occur in a tertiary manner but this is very rare

 

Primary hyperparathyroidism

• The most common endocrine disorder and an important cause of hypercalcaemia
• May be due to;
  • Adenoma – 80%
  • Primary hyperplasia (diffuse or nodular) – 15%
  • Parathyroid carcinoma – < 5%
• Usually a disease of adults, F>M 3:1
• Usually occurs after age 50

 

• The genetic syndromes associated with familial hyperparathyroidism include;
  • Multiple endocrine neoplasia – 1 (MEN-1). The gene for which is on chromosome 11 and encodes for a tumour suppressor gene
  • Multiple endocrine neoplasia – 2 (MEN-2). Caused by activating mutations in the tyrosine kinase RET, on chromosome 10
  • Familial hypocalciuric hypercalcaemia (FHH). An autosomal dominant disorder characterised by enhanced parathyroid function. The primary cause for this disorder is mutations in the parathyroid calcium sensing receptor gene (CASR) on chromosome 3. Patients who are homozygous present in the neonatal period with severe hyperparathyroidism

 

• Most sporadic parathyroid adenomas are monoclonal suggesting they are true neoplastic outgrowths from a single progenitor cell
• Sporadic parathyroid hyperplasia is also monoclonal in many instances especially when associated with perisitant stimulus for parathyroid growth
• Among the sporadic adenomas there are two molecular defects with an established role in pathogenesis
  • Parathyroid adenoma 1 (PRAD1) encodes cyclin D1 a major regulator of the cell cycle. An inversion on chromosome 11 results in a relocation of PRAD1  so that it is adjacent to the PTH gene
  • MEN1, the spectrum of MEN1 mutations in sporadic tumours is virtually identical to that of familial parathyroid adenomas

 

Morphology

• Parathyroid adenomas are generally solitary, well-circumscribed and invested by a delicate capsule
• In contrast to primary hyperplasia, the glands outside the adenoma are generally normal in size or perhaps shrunken due to feedback inhibition by elevated serum calcium
• The adenomas are generally composed of uniform chief cells but some oxyphil cells may be present

 

• Primary hyperplasia may occur sporadically or as a component of MEN syndrome. All four glands are involved although generally asymmetrically
• The most common histological finding is chief cell hyperplasia
• In many instances there are islands of oxyphilsand there may be poorly developed fibrous stands enveloping the nodules

 

• Parathyroid carcinoma may be fairly well circumscribed and therefore difficult to distinguish with adenomas or they may be clearly invasive. The tumours enlarge one parathyroid gland and histologically the cells are uniform and resemble normal parathyroid cells. The diagnosis of carcinoma based on cytology is unreliable and invasion and metastases are the only reliable criteria of malignancy

 

• Skeletal changes include prominence of osteoclasts which erode bone matrix and mobilise calcium salts particularly in the metaphysic of long tubular bones
• There may be increased osteoblastic activity and formation of new bone trabeculae, which may be widely spaced and delicate looking, similar to that of osteoporosis
• In severe cases the cortex is grossly thinned and the marrow contains increased amounts of fibrous tissue accompanied by haemorrhage and cyst formation – osteitis fibrosa cystica
• Aggregates of osteoclasts, reactive giant cells and haemorrhagic debris can form masses that can be mistaken for tumours – called brown tumours of hyperparathyroidism

 

• Formation of urinary tract stones may occur as well as calcification of the renal interstitium (nephrolithiasis) and tubules (nephrocalcinosis)

 

• Metastatic calcification secondary to hypercalcaemia may also be seen in other sites including the stomach, lungs, myocardium and blood vessels

 

Clinical course

• May be asymptomatic or symptomatic
• Asymptomatic hyperparathyroidism
  • Generally discovered after routine blood tests
  • In primary hyperparathyroidism serum PTH levels are inappropriately high
  • In hypercalcaemia because of non-parathyroid diseases the PTH levels are low
• Symptomatic primary hyperparathyroidism
  • “Painful bones, renal stones, abdominal groans and psychic moans”
  • Clinical manifestations are;
    • Bone disease
    • Nephrolithiasis (renal stones)
    • GI disturbances – constipation, nausea, peptic ulcers, pancreatitis and gallstones
    • Neuromuscular disturbances including weakness and fatigue
    • Cardiac manifestations including mitral and/or aortic valve calcifications
  • The abnormalities related to hyperparathyroidism are nephrlithiasis and bone disease
  • The symptoms due to hypercalcaemia are fatigue, weakness and constipation

 

Causes of hypercalcaemia

• Raised PTH
  • Hyperparathyroidism – primary, secondary and tertiary (secondary and tertiary are mostly associated with renal failure)
  • Familial hypocalciuric hypercalcaemia
• Decreased PTH
  • Hypercalcaemia of malignancy
  • Vit D toxicity
  • Immobilisation
  • Thiazide diuretics
  • Granulomatous disease (sarcoidosis)

 

Secondary hyperparathyroidism

• Caused by any condition associated with a chronic depression in the serum calcium level because low serum calcium levels leads to compensatory over activity of the parathyroids
• Renal failure is the most common cause
• Other causes include;
  • Dietary calcium deficiency
  • Steatorrheoa
  • Vitamin D deficiency
• Chronic renal insufficiency is associated with decreased phosphate excretion and the resulting phosphataemia can suppress serum calcium levels and thereby stimulate the parathyroid gland
• In addition the loss of renal substance reduces the availability of the α1-hydroxylase required fro the synthesis of the active form of Vit D which in turn reduces the intestinal reabsorption of calcium

 

Morphology

• Parathyroid glands are hyperplastic with asymmetrical enlargement
• There is increased numbers of chief cells and fewer fat cells
• Bone changes similar to those seen in primary hyperparathyroidism may be present
• Again metastatic calcification may be seen in tissues such as the heart, lungs, stomach and blood vessels

 

Clinical course

• Clinical features are generally dominated by the renal failure
• The bone abnormalities are generally less severe than those seen in the primary hyperparathyroidism
• The vascular calcification may occasionally result in ischaemic damage to skin and other organs. This is referred to as calciphylaxis

 

• In a minority of patients parathyroid activity may become autonomous and excessive with resultant hypercalcaemia. This is called tertiary hyperparathyroidism. Parathyroidectomy may be required in such patients