Endocrinology - Parathyroids

Question 1

How is calcium transported in the blood?

Answer 1

40% of the total Ca++ in the blood is bound to plasma proteins. 60% of the total Ca++ in the blood is not bound to proteins and is ultrafilterable. Ultrafilterable Ca++ includes Ca++ that is complexed to anions such as phosphate and free ionized Ca++.

It is the free ionized Ca++ that is physiologically active.
To maintain Ca++ balance, intestinal absorption must be balanced by renal excretion.

Question 2

Where is parathyroid hormone secreted?

Answer 2

PTH is the major hormone for the regulation of serum Ca++. It is synthesised and secreted by the chief cells of the parathyroid glands in response to low serum Ca++.

Question 3

What controls secretion of PTH?

Answer 3

Secretion of PTH is controlled by the serum Ca++ binding to Ca++ sensing receptors in the parathyroid cell membrane. Decreased serum Ca++ increases PTH secretion, whereas increased serum Ca++ decreases PTH secretion.

Mild decreases in serum Mg++ also stimulate PTH. Severe decreases in serum Mg++ inhibit PTH secretion and produce symptoms of hypoparathyroidism (i.e. hypocalcaemia).

The second messenger for PTH secretion by the parathyroid glands is cAMP.

Question 4

What is the overall action of PTH? How does it achieve this?

Answer 4

The overall effect of PTH is an increase in serum Ca++ and a decrease in serum phosphate. The second messenger for PTH actions on target tissue is cAMP.

PTH achieve this by 4 main actions:
1) Increases bone resorption which brings both Ca++ and phosphate from bone mineral into ECF. Alone this effect would not increase the serum ionized [Ca++] because phosphate complexes with Ca++. Resorption of the organic matrix of bone is reflected by increased hydroxyproline excretion

2) Inhibits renal phosphate reabsorption in the proximal tubule and therefore increases phosphate excretion. As a result the phosphate reabsorbed from bone is excreted in the urine, allowing the serum ionized Ca++ to increase. cAMP generated as a result of the action of PTH in the renal tubule is excreted in the urine (urinary cAMP)
3) PTH increases renal Ca++ reabsorption in the distal tubule which also increases the serum Ca++
4) PTH increases intestinal Ca++ absorption indirectly by stimulating the production of 1,25 - dihydroxycholecalciferol in the kidney

Question 5

What is the main function of vitamin D? What does vit D deficiency cause in adults and children?

Answer 5

It provides Ca++ and phosphate to ECF for bone mineralization. In children vitamin D deficiency causes rickett’s, in adults this is called osteomalacia.

Question 6

How is vitamin D synthesised?

Answer 6

Dietary vitamin D and 7 -dehydrocholesterol are converted into cholecalciferol (by UV light for the latter). The liver converts this into 25-OH-cholecalciferol which the kidney then converts into 1,25-dihydroxycholecalciferol using the enzyme 1 alpha hydroxylase. This is the active form of vitamin D.

1 alpha hydroxylase activity is increased by:

• decreased serum Ca++
• PTH
• decreased serum phosphate

Question 7

What are the actions of vitamin D?

Answer 7

Overall these are co-ordinated to increase both Ca++ and phosphate in ECF to mineralise new bone. This is achieved by the following:

1) Increases intestinal Ca++ absorption - vitamin D dependent Ca++ binding protein (calbindin D-28k) is induced by 1,25-dihydroxycholecalciferol
- PTH increases intestinal Ca++ absorption indirectly by stimulating 1 alpha hydroxylase activity and increasing production of the active form of vit D

2) Increases intestinal phosphate absorption
3) Increases renal reabsorption of phosphate and Ca++, analogous to its actions on the intestine
4) Increases bone resorption which provides Ca++ and phosphate from “old” bone to mineralise “new” bone

Question 8

What is calcitonin? Where is it secreted from?

Answer 8

Calcitonin is a hormone secreted from the parafollicular cells of the thyroid gland. Secretion is stimulated by an increase in serum Ca++. It acts primarily to inhibit bone resorption and can be used to treat hypercalcaemia.

Question 9

What is corrected calcium?

Answer 9

Labs usually measure total plasma calcium, but 40% is bound to albumin. The rest is the ultrafiltratable portion, some of which is free ionised and the physiologically important fraction. Therefore, correct total Ca++ for albumin as follows: add 0.1mmol/L to Ca++ level for every 4g/L that albumin is below 40g/L and a similar subtraction for raised albumin.

Question 10

Besides the overproduction of parathyroid hormone, what are the other major causes of hypercalcaemia?

Answer 10

The most important causes of hypercalcaemia are:

• Parathyroid hormone excess
• Parathyroid related protein excess
• Tumours

Question 11

What is PTH related protein?

Answer 11

Parathyroid hormone related protein (PTHrP) is a polypeptide normally produced by squamous epithelial cells of the skin. It binds to receptors for PTH and thus has the same effects on calcium homeostasis as PTH. PTHrP is the cause of hypercalcaemia in patients with squamous cell carcinomas most often originating from the bronchi, breast or renal cell carcinomas.

Malignant tumours metastatic to the bones cause hypercalcaemia by directly destroying bone or indirectly by activating osteoclasts through the production of tumour necrosis factor alpha or IL-1.

Question 12

What are the signs and symptoms of hypercalcaemia?

Answer 12

This can be remembered using the aid memoire, “bones, stones, moans and groans”:

• abdominal pain
• vomiting
• constipation
• polyuria; polydipsia
• depression (psychic moans)
• weight loss
• hypertension (always check Ca++ in high BP!)
• renal stones
• ectopic calcification
• QT interval prolongation on ECG

Question 13

How is hypercalcaemia investigated?

Answer 13

The main distinction that must be made is malignancy vs primary hyperparathyroidism. Pointers to malignancy are:

• decreased albumin
• decreased chloride
• alkalosis
• decreased K+
• raised phosphate
• increased alk phos

Raised PTH, high serum calcium and low serum phosphate indicate hyperparathyroidism.

Question 14

In a patient with symptoms of hypercalcaemia and raised albumin what is the likely underlying cause?

Answer 14

This is fairly simple. The next step should be to check the patients urea. Raised Ca++, raised albumin and high urea points towards dehydration. If the urea is normal then the specimen is likely to be cuffed. Repeat.

Question 15

What is the likely cause of hypercalcaemia in a patient with normal or low albumin?

Answer 15

Remember that the most common causes of hypercalcaemia are PTH excess, PTHrP excess and tumours.

A normal or low albumin should be followed by checking the patients phosphate. If the phosphate is decreased or normal and the urea is also normal then the likely diagnosis is primary or tertiary hyperparathyroidism.

If the phosphate is high or normal then it is useful to check the alkaline phosphatase:
(i) raised alk phos (e.g. from increased bone turnover) = bone metastases, sarcoidosis, thyrotoxicosis or lithium toxicity

(ii) normal alk phos = myeloma (plasma protein incr.), vitamin D excess, sarcoidosis, increased bicard points to milk-alkali syndrome

Question 16

What is classed as acute hypercalcaemia?

Answer 16

This is when the calcium is > 3.5mmol/L and the patient is symptomatic. Treatment is as follows:
1) Correct dehydration (if present) with 0.9% saline

2) Bisphosphonates prevent bone resorption by inhibiting osteoclast activity. A single dose of pamidronate lowers Ca++ over 2-3d, maximum effect is at 1wk. Infuse slowly. SE: flu symptoms, reduced phosphate, bone pain, myalgia, nasuea, lymphocytopaenia, decreased Mg, decreased Ca++, seizures
3) Further management - treat the underlying cause, e.g. chemotherapy in malignancy, steroids in sarcoidosis, diuretics only when the patient is fully hydrated as they may exacerbate hypercalcaemia by worsening dehydration

Question 17

What is the most common cause of hyperparathyroidism?

Answer 17

Hyperparathyroidism is most often caused by a parathyroid adenoma, which accounts for 80% of cases. Primary hyperparathyroid hyperplasia accounts for 15-20% and parathyroid carcinoma accounts for 5%. Approximately 10-20% of sporadic adenomas are associated with a mutation of parathyroid adenoma 1 protooncogene located on chromosome 11 next to the PTH regulatory gene.

Question 18

How are parathyroid adenomas distinguished morphologically from parathyroid hyperplasia or parathyroid carcinoma?

Answer 18

Parathyroid adenomas present as nodular enlargement of one parathyroid gland, whereas the size of the other three glands remains normal. Occasionally a rim of compressed normal parathyroid may be seen at one pole of the adenoma or carcinoma. In contrast, parathyroid hyperplasia leads to an enlargement of all four parathyroid glands. Parathyroid carcinomas may be indistinguishable from parathyroid adenomas, and the only definitive sign that a tumor is malignant is the presence of metastases. Histologic examination of parathyroids is of limited value: both the adenomas and carcinomas and the hyperplastic parathyroids are composed of relatively uniform “water-clear” or oxyphil cells. These cells “squeeze out” the fat cells normally found in the parathyroid glands.

Question 19

What are the pathologic changes caused by hyperparathyroidism?

Answer 19

Hyperparathyroidism causes changes in several organs:

Bone erosion and restructuring (Osteoclasts stimulated by PTH cause resorption of bone trabeculae). At the same time, there is increased osteoblastic activity and new bone formation. Fragile bones fracture easily, causing bleeding, fibrosis, and osteoclastic resorption of bone (osteitis fibrosa cystica). In severe cases, osteoclasts and fibroblasts form tumorlike lesions resembling giant cell tumors of bone, known as brown tumor of hyperparathyroids.)

Renal calcification and stone formation

Metastatic calcifications in various sites

Question 20

Name some other causes of metastatic (ectopic) calcification

Answer 20

Remember the mnemonic “PARATTHORMONE”
PTH (increased) and other causes of raised Ca++, e.g. sarcoidosis
Amyloidosis
Renal failure (relates to raised phosphate)
Addisson’s disease (adrenal calcification)
TB
Toxoplasmosis
Histoplasmosis (e.g. in lungs)
Overdose of vitamin D
Raynaud’s associated disease (e.g. CREST, dermatomyositis)
Muscle primaries/ leiomyosarcomas
Ossifying metastases (osteosarcoma or ovarian mets)
Nephrocalcinosis
Endocrine tumours

Question 21

What are the clinical signs of primary hyperparathyroidism?

Answer 21

The laboratory findings are diagnostic and include increased serum ionized calcium, low phosphorus, and high parathyroid hormone. Clinical symptoms are, in part, due to the pathologic changes in the bones and kidneys as well as functional changes in the gastrointestinal tract (constipation, nausea, peptic ulcer, and pancreatitis) and neuromuscular disorders (muscle weakness, depression, lethargy, and even seizures). These manifestations of hyperparathyroidism are known as “painful bones, renal stones, abdominal groans, and mental moans.

BP is also increased so check Ca++ in everyone with hypertension.

Question 22

How is primary hyperparathyroidism treated? What are the indications for surgery?

Answer 22

Similar to the treatment of hypercalcaemia. If mild, advise increased fluid intake to prevent stones, avoid thiazide diuretics + high Ca++ and vit D intake and see 6 monthly.

Excision of the adenoma or of all 4 hyperplastic glands prevents fractures and peptic ulcers. Indications: high serum or urinary Ca++, bone disease, osteoporosis, renal calculi, decreased renal function or age <50 year.

Question 23

What are the complications of surgery for hyperparathyroidism?

Answer 23

Hypoparathyroidism, recurrent laryngeal nerve palsy (therefore hoarseness) , and symptomatic low calcium are well known complications. Pre op ultrasound and MIBI scan may localise an adenoma. Intra-operative PTH sampling is used to confirm removal. Recurrence is 8% over 10 years.

Question 24

Are there any alternatives to surgery in primary hyperparathyroidism?

Answer 24

Cinacalcet ( a “calcimimetic”) increases sensitivity of parathyroid cells to Ca++ therefore decreasing PTH secretion. SE include myalgia and decreased testosterone. Monitor Ca++ within 1 week of dose changes.

Question 25

What is the main cause of secondary hyperparathyroidism?

Answer 25

It is chronic renal failure. End-stage kidney disease impairs the excretion of phosphate, causing hyperphosphatemia, which depresses the serum calcium. Low levels of serum calcium trigger a release of PTH and parathyroid hyperplasia, which develops over time. An excess of PTH will cause bone lesions (renal osteodystrophy) similar to, but usually less severe than, those found in primary hyperparathyroidism. Laboratory findings include high PTH, high calcium, and high phosphate levels.

Question 26

What is tertiary hyperparathyroidism?

Answer 26

Secondary hyperparathyroidism of chronic renal failure usually recedes following renal transplantation or efficient renal dialysis. If the stimulated parathyroids remain active even after the metabolic consequences of renal disease have been corrected, a parathyroidectomy may be the only way to correct this tertiary hyperparathyroidism.

Question 27

What is the most common cause of hypoparathyroidism?

Answer 27

Hypoparathyroidism is a rare disorder that is most often caused by accidental parathyroidectomy during neck surgery for thyroid or other cancer. Some patients treated surgically for primary hyperparathyroidism develop hypoparathyroidism.

Congenital parathyroid aplasia in DiGeorge syndrome, mutations of the calcium-sensing receptor (PCAR1), and destruction of parathyroids in pluriglandular autoimmune and familial endocrine insufficiency syndrome are rare causes of hypoparathyroidism.

Question 28

What are the clinical signs of primary hypoparathyroidism?

Answer 28

Diagnostic laboratory findings include low serum calcium, high phosphate, and low PTH concentration. Hypocalcemia leads to increased neuromuscular irritability and hyperreflexia, which can be demonstrated by eliciting the Chvostek or Trousseau signs. Mental and neurologic symptoms predominate and include depression, paranoia, and signs of intracranial hypertension. Cataracts develop due to calcifications of the lenses. Cardiac conduction defects are common.

Question 29

How is hypoparathyroidism treated?

Answer 29

All forms of hypoparathyroidism respond well to supplementation of diet with calcium and vitamin D.
In chronic kidney disease the patient may require alfacalcidol

Question 30

What is secondary hypoparathyroidism?

Answer 30

This is reduced levels of PTH secretion secondary to radiation, surgery (e.g. thyroidectomy, parathyroidectomy), hypomagnesaemia (magnesium is required for PTH secretion).

Question 31

What is pseudohypoparathyroidism?

Answer 31

This is failure of a target cell to respond to PTH. Signs include short metacarpals (esp 4th and 5th digits), round face, short stature, and calcified basal ganglia. Diagnostic tests show decreased Ca++, raised PTH, normal or increased alk phos.

Question 32

What are the features of hypocalcaemia?

Answer 32

This can be remembred using the aid memoire “SPASMODIC”
Spasms (carpopedal spasms = Trousseau’s sign)
Perioral paraesthesia
Anxious, irritable, irrational
Seizures
Muscle tone increase in smooth muscle - hence colic, wheeze, dysphagia
Orientation impaired
Dermatitis
Impetigo hepatoformis (decreased calcium and pustules in pregnancy - rare and serious)
Chovstek’s sign, choreoathetosis, cataract, cardiomyopathy

Question 33

What causes hypocalcaemia in a patient with normal or decreased phosphate?

Answer 33

Osteomalacia (increased alk phos)
Acute pancreatitis
Over hydration
Respiratory alkalosis (total Ca++ is normal but ionised fraction is decreased due to increased pH therefore symptomatic)

Question 34

How many parathyroid glands are there usually?

Answer 34

There are normally 4 parathyroid glands - 1 superior, 1 inferior and 2 on either side. But the number can be as many as 6. 90% are in close relationship with the thyroid, 10% are aberrant (invariably being the inferior glands).

The superior thyroid glands are usually located above the level at which the inferior thyroid artery crosses the recurrent laryngeal nerve in the middle of the posterior lobe of the thyroid.

Question 35

How do the parathyroids develop?

Answer 35

The superior parathyroids differentiate from the 4th branchial pouch. The inferior glands develop from the 3rd pouch in company with the thymus. As the latter descends the inferior parathyroids are dragged down with it.

It is thus easily understood that the inferior parathyroid glands may be dragged beyond the thyroid into the mediastinum and why, although very rarely parathyroid tissue is found in the thymus.

Question 36

Are the parathyroids safe during subtotal thyroidectomy?

Answer 36

Yes, because the posterior rim of the thyroid is preserved. However, they may be inadvertently removed or damaged, with resultant tetany due to lowered serum calcium.