I have recently wrote this for meducation.net. Enjoy!
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Calcium Metabolism Disorders
author: Chan En Ze, MBBS
date: 13 October 2013
What are the functions of calcium in our body?
Calcium has numerous functions in our body and can broadly divide into two:
1) The first role is calcium act as structural support in the form of bone. A bone is composed of 35% organic matrix (mostly proteins in the form of Collagen) and 65% inorganic calcium hydroxyapatite (hy·droxy·ap·a·tite). When you put a bone under a flame, the organic part will be all burnt up, and what remains is the inorganic calcium hydroxyapatite, which gives the white chalky texture. The Calcium Hydroxyapatite has the biochemical formula Ca5(PO4)3(OH) which shows that it composed of both calcium (Ca) and phosphate (PO4), thus regulation and metabolism of Calcium in our body is closely related to the regulation and metabolism of Phosphate. It is interesting to note that some orthopedic prosthetic implants are coated with Calcium Hydroxapatite to promote osseointegration.
2) The second role is it maintains normal cellular function: neuromuscular signalling,hormone release, cardiac contractility, and blood coagulation. That is why, the calcium concentration in our blood is maintained within a narrow range (2.2-2.7mmol/l) because any small disturbance of the concentration will greatly affect the muscle, nervous system, endocrine, heart and blood coagulation. The details of these mechanism is beyond the scope of this chapter.
How calcium regulation take place in our body?
The four main organs which tightly regulate calcium in our body are the intestine, bone, kidney and parathyroid glands. For simplicity sake, think of the intestine takes in all the calcium into our body, bone act as a huge store room for calcium, kidney as calcium disposer, and the parathyroid that secretes parathyroid hormone (PTH) maintains the blood calcium concentration.
There are 2 main hormones which tightly regulate calcium concentration:
1) The parathyroid hormone(PTH) secreted by parathyroid gland which regulate blood calcium concentration minute by minute. Increase of PTH will increase calcium concentration and vice versa. The only way to get calcium supply in this short amount of time is to get it from the bone and to immediately decrease kidney secretion of calcium ion. You can’t count on the intestine to wait for supply of calcium in the next meal! That is why after a total thyroidectomy done, a surgeon will measure the corrected serum calcium the following day after the surgery. If the parathyroid is affected, there will be a quick decrease in serum calcium concentration the following day. I say “corrected” because calcium is bounded to albumin in plasma, hence we need to take albumin concentration into account.
2) Unlike the PTH, the Vitamin D has a more long term role on calcium regulation. It has the major role on calcium absorption in the intestine and lesser role on the bone and kidney. With the help of Vitamin D, these absorbed calcium is then stored in the bone. Another way of thinking the Vitamin D is it act as “bone builder”, it increases calcium and phosphate absorption to the bone and decrease excretion of calcium and phosphate in the kidney. This is contrast to PTH which breakdown the bone by releasing calcium and phosphate into the blood, decrease calcium excretion in the kidney but increase phosphate excretion.
The Vitamin D is obtained from diet and synthesis in the skin by the action of sunlight. It is serially activated to 25-hydroxylation in the liver and 1-hydroxylation in the kidney. That is why decrease in sunlight exposure, liver and kidney failure will affect Vitamin D concentration.
In the “mind” of the hormones
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Parathyroid hormone
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Vitamin D
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My Goals
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My goal is to regulate serum calcium concentration minute by minute by increase serum calcium in a very short time.
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My goal is to build strong bones and long term calcium regulation.
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How I do it?
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Breakdown bone, increase calcium and phosphate release into the blood. Increase decrease excretion of calcium in the kidney but increase phosphate excretion in the kidney
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Activate the intestine to absorb dietary calcium. Build bone by increase calcium and phosphate absorption in the bones. It also need increase supply of both calcium and phosphate by decrease excretion of both ions in the kidney.
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The other hormone is the Calcitonin (produced by the C-cell of the thyroid) act exactly opposite to the PTH, but has less physiologic importance.
What are the causes of too much calcium in our blood (hypercalcemia)?
The causes of hypercalcemia are increase calcium intake, increase calcium release from the bone, and other causes.
Increase calcium intake:
1) Excessive ingestion of OTC medicine Calcium Carbonate to treat dyspepsia. This is known as Milk-Alkali Syndrome. This is more markedly in pregnancy when there is increase absorption of calcium in the guts.
2) Total parenteral nutrition
3) Vitamin D intoxication
4) Excessive Vitamin D production in granulomatous disease like sarcoidosis, tuberculosis, and silicosis. In these lesions, there are excessive macrophages which produce Vitamin D, which in turn activate the gut to absorb calcium.
Increase calcium release from the bone:
1) One most important cause is hyperparathyroidism. Primary hyperparathyroidism is when there is single or multiple parathyroid adenomas or hyperplasia causing increase secretion of PTH inspite of already high calcium concentration in the blood. In normal condition when serum calcium is high, the feedback mechanism causes decrease secretion of PTH. However, in primary hyperparathyroidism, there is increase in serum calcium and normal or high, PTH level. There is also increase urinary calcium, decrease in serum phosphate due to its action on the kidney. Because of the action of PTH, there is increase bone resorption, activation of osteoblast and osteoclast which results in high alkaline phosphatase level, resorption cavities in the bones (known as osteatitis fibrosa cystica) and bone marrow fibrosis. Treatment for this condition is to surgically remove the parathyroid gland. In familial cases, hyperparathyroidism is associated with MEN type 1, a neoplastic lesion of pituitary, parathyroid, and pancreas.
2) Parathyroid carcinoma can results in increase PTH production and hence, hypercalcemia.
3) In renal failure, there is decrease production of activated Vitamin D which cause prolonged hypocalcemia state. This cause compensatory hypertrophy of the parathyroid gland. In this case, the PTH level is high, but the calcium level remains low or normal. This is known as the Secondary hyperparathyroidism. In long setting of this condition where there is parathyroid hyperplasia, eventually blood calcium level is raised. This condition is known as tertiary hyperparathyroidism.
4) Lytic skeletal metastases in malignancies such breast cancer and myeloma
5) Many solid tumours like squamous cell carcinoma of lung secrete Parathyroid Hormone-related Protein (PTHrP) which behaves like PTH and causes hypercalcemia. This may be the first sign of malignancy and is consider a paraneoplastic syndrome.
6) Hyperthyroidism can cause hypercalcemia but the exact mechanism is not understood. Thyroid hormone is known to stimulate osteoclast differentiation and hence increase bone resorption causing hypercalcemia.
7) Like wise, prolonged immobilisation increase bone resorption causing hypercalcemia.
Other causes:
1) In the parathyroid gland, there are calcium sensor receptor (CaSR) which sense the calcium concentration level and in return the parathyroid gland will secrete the appropriate amount of PTH. Mutations that reduce the activity of this receptor can result in higher concentration of calcium and PTH. THis condition is known as Familial hypocalciuric hypercalcaemia.
2) Lithium therapy also can affect the function of CaSR and causing hypercalcemia.
3) Endocrine disorder such as Addison’s disease, Pheochromocytoma, VIPoma
4) Medication such as thiazides, Vitamin A toxicity,, Theophylline toxicity.
What are the causes of too little calcium in our blood (hypocalcemia)?
The cause of hypocalcemia can be divided into two categories: hypocalcemia with low serum PTH level (hypoparathyroidism) and hypocalcemia with high serum PTH level (secondary hyperparathyroidism).
Low Parathyroid Hormone Levels. This is due to defective in the parathyroid gland itself. Failure of PTH production cause decrease serum calcium level. The causes are of low PTH hypocalcemia are the following:
1)Parathyroid destruction can be spontaneous due to autoimmune causes. Autoimmune hypoparathyroidism can be associated with autoimmune polyglandular syndrome type 1 (mucocutaneous candidiasis, adrenal, gonadal, thyroid failure)
2) Post radiation, post surgery like parathyroidectomy and thyroidectomy, infiltration by metastases or systemic disease; all these can cause low PTH
3) Hypomagnesemia can impaired synthesis and secretion of PTH. Hypomagnesemia is always associate with hypocalcemia and hypokalemia.
4) Previously, we mention CaSR. Mutation that reduce the activity of CaSR can cause hypercalcemia in case of familial hypocalciuric hypercalcaemia; in contrast, mutation that increase the activity of CaSR can cause hypocalcemia and this condition is called autosomal dominant hypocalcaemia with hypercalciuria.
5) Parathyroid agenesis like DiGeorge syndrome (mnemonic CATCH-22: cardiac anomaly, abnormal facies, thymic aplasia, cleft palate, hypoparathyroidism - Chromosome 22 abnormality)
High Parathyroid Hormone Levels. The parathyroid gland is fine, but there are other factor which cause hypocalcemia. Hence, to compensate, there is overactivity of parathyroid gland. The causes of high PTH hypocalcemia are the following:
1) Vitamin D deficiency can occurs in malabsorption, dietary deficiencies, lack of sunlight..Vitamin D resistance including receptor defects (vitamin D dependent rickets type ii) can cause hypocalcemia. In chronic renal failure, there is impaired production of activated vitamin D and hence causes hypocalcemia.
2) Also, in chronic renal failure, there is hyperphosphataemia. When phosphate level is high, it will precipitate ionising calcium and cause serum hypocalcemia. This is why hyperphosphataemia will cause ectopic deposition of calcium in tissues. The other causes of hyperphosphataemia besides chronic renal failure are acute rhabdomyolysis, tumour lysis syndrome, phosphate administration.
3) Deposition of calciums also can occurs in pancreatitis, hungry bone syndrome following parathyroidectomy.
4) Pseudo-hypoparathyroidism is when the parathyroid gland and secretion of PTH is normal but there is PTH resistance. Pseudo-hypoparathyroidism is due to G protein mutations with a characteristic of short stature, short metacarpals, and intellectual impairments.
4) Drugs can cause hypocalcemia by precipitate serum calcium are like EDTA. Some drugs like bisphosphonate inhibits bone resorption causes hypocalcemia. Phenytoin and ketoconazole can altered vitamin D metabolism which causes hypocalcemia.
What happen if there is too much Calcium in our blood?
We know that calcium is important in the signalling process in nervous system and neuro-muscular junction. Hence patients with hypercalcemia will experience, neuropsychiatric symptoms like depression, decrease concentration, personality changes, lethargy, confusion and muscle weakness. Calcium is also important in cardiac contractility, hence in hypercalcemia especially in acute hypercalcemia, there will be bradycardia, AV block, short QT interval. That is why administering calcium intravenously is done slowly and in diluted form (rules of 10: 10ml Calcium gluconate dilute 10ml of 10% Dextrose given in 10 minutes) and with monitor attached on the patient. Hypercalcemia also can cause gastrointestinal symptoms like nausea, anorexia, constipation. It also can cause pancreatitis. Hypercalcemia can increase gastrin production and causes peptic ulcer disease. Hypercalcemia decreases renal concentration ability which cause nephrogenic diabetes insipidus where there is polyuria and polydipsia. Hypercalcemia which cause hypercalciuria also can cause renal stones (nephrolithiasis). Hypercalcemia due to long standing elevated PTH can cause bone pain. The easy way to remember all these symptoms of hypercalcemia is to remember this mnemonic: "stones, bones, abdominal groans and psychiatric moans"
The treatment for acute hypercalcemia is adequate hydration, intravenous disphosphonates and identify the underlying cause and treat appropriately.
What happen if there is too little Calcium in our blood?
Calcium ion is important signalling process in nervous system and neuro-muscular junction and in hypocalcemia, there will be neuromuscular disturbance like muscle spasm, tetany, seizure, confusions, neuropsychiatric and myelopathy. Signs in hypocalcemia including on tapping the facial nerve causes twitching of the facial muscle (Chvostek’s Sign) and sphygmomanometer-induce ischaemia causing carpopedal spasm (Trousseau’s sign). Hypocalcemia can affect cardiac contractility which cause prolonged QT syndrome. Chronic hypocalcemia can affects bones growth like rickets and osteomalacia. It also can impair dental growth. There will be dry skin, brittle nails, and hair loss. It also known to cause cataracts in chronic hypocalcemia.
Treatment for hypocalcemia including calcium replacement: intravenous calcium gluconate infusion if severe hypocalcemia or oral calcium supplements if less severe. Vitamin D supplement for Vitamin D deficiency, renal failure, and hypoparathyroidism. Thiazide diurectics and low salt diet can increase calcium level. Recombinant human 1-34PTH is available but the cost is prohibitive.
References:
1) Harvey R et al (2010) Biochemistry (Lippincott's Illustrated Reviews Series), Chapter 28 Vitamins
2) Khosla S (2008) Harrison's Principles of Internal Medicine, 17th Edition Vol 1 , Chapter 47 Hypercalcemia and Hypocalcemia
3) Kalra P (2009) Essential Revision Notes for MRCP Third Edition, Chapter 13.5 Disorders of bone, mineral metabolism and inorganic ions.
