Flashcards in Endocrinology - Parathyroids Deck (36):
How is calcium transported in the blood?
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.
Where is parathyroid hormone secreted?
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++.
What controls secretion of PTH?
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.
What is the overall action of PTH? How does it achieve this?
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
What is the main function of vitamin D? What does vit D deficiency cause in adults and children?
It provides Ca++ and phosphate to ECF for bone mineralization. In children vitamin D deficiency causes rickett's, in adults this is called osteomalacia.
How is vitamin D synthesised?
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++
- decreased serum phosphate
What are the actions of vitamin D?
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
What is calcitonin? Where is it secreted from?
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.
What is corrected calcium?
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.
Besides the overproduction of parathyroid hormone, what are the other major causes of hypercalcaemia?
The most important causes of hypercalcaemia are:
- Parathyroid hormone excess
- Parathyroid related protein excess
What is PTH related protein?
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.
What are the signs and symptoms of hypercalcaemia?
This can be remembered using the aid memoire, "bones, stones, moans and groans":
- abdominal pain
- polyuria; polydipsia
- depression (psychic moans)
- weight loss
- hypertension (always check Ca++ in high BP!)
- renal stones
- ectopic calcification
- QT interval prolongation on ECG
How is hypercalcaemia investigated?
The main distinction that must be made is malignancy vs primary hyperparathyroidism. Pointers to malignancy are:
- decreased albumin
- decreased chloride
- decreased K+
- raised phosphate
- increased alk phos
Raised PTH, high serum calcium and low serum phosphate indicate hyperparathyroidism.
In a patient with symptoms of hypercalcaemia and raised albumin what is the likely underlying cause?
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.
What is the likely cause of hypercalcaemia in a patient with normal or low albumin?
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
What is classed as acute hypercalcaemia?
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
What is the most common cause of hyperparathyroidism?
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.
How are parathyroid adenomas distinguished morphologically from parathyroid hyperplasia or parathyroid carcinoma?
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.
What are the pathologic changes caused by hyperparathyroidism?
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
Name some other causes of metastatic (ectopic) calcification
Remember the mnemonic "PARATTHORMONE"
PTH (increased) and other causes of raised Ca++, e.g. sarcoidosis
Renal failure (relates to raised phosphate)
Addisson's disease (adrenal calcification)
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)
What are the clinical signs of primary hyperparathyroidism?
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.
How is primary hyperparathyroidism treated? What are the indications for surgery?
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.
What are the complications of surgery for hyperparathyroidism?
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.
Are there any alternatives to surgery in primary hyperparathyroidism?
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.
What is the main cause of secondary hyperparathyroidism?
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.
What is tertiary hyperparathyroidism?
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.
What is the most common cause of hypoparathyroidism?
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.
What are the clinical signs of primary hypoparathyroidism?
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.
How is hypoparathyroidism treated?
All forms of hypoparathyroidism respond well to supplementation of diet with calcium and vitamin D.
In chronic kidney disease the patient may require alfacalcidol
What is secondary hypoparathyroidism?
This is reduced levels of PTH secretion secondary to radiation, surgery (e.g. thyroidectomy, parathyroidectomy), hypomagnesaemia (magnesium is required for PTH secretion).
What is pseudohypoparathyroidism?
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.
What are the features of hypocalcaemia?
This can be remembred using the aid memoire "SPASMODIC"
Spasms (carpopedal spasms = Trousseau's sign)
Anxious, irritable, irrational
Muscle tone increase in smooth muscle - hence colic, wheeze, dysphagia
Impetigo hepatoformis (decreased calcium and pustules in pregnancy - rare and serious)
Chovstek's sign, choreoathetosis, cataract, cardiomyopathy
What causes hypocalcaemia in a patient with normal or decreased phosphate?
Osteomalacia (increased alk phos)
Respiratory alkalosis (total Ca++ is normal but ionised fraction is decreased due to increased pH therefore symptomatic)
How many parathyroid glands are there usually?
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.
How do the parathyroids develop?
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.