(Vitamin D is a group of fat-soluble compounds with a four-ringed cholesterol backbone. First described by Whistler and Glisson in the mid 1600s, vitamin D is now recognized as a prohormone.) Vitamin D exists in two major forms: vitamin D2 (ergocalciferol) and vitamin D3 (cholecalciferol). The precursor for vitamin D2 is a plant sterol ergosterol. D2 can be synthesized by ultraviolet irradiation of ergosterol from yeast. Similarly, vitamin D3 is synthesized in the body when sunlight (ultraviolet B, wavelength 280-315 nm) photoisomerizes 7-dehydroxycholesterol found in the skin. D3 is also found in animal-based foods (eg, fatty fish, liver, milk, eggs). (Vitamin D2 and D3, regardless of the source, are biologically inactive. They have to be transformed into the biologically active molecule 1,25 dihydroxyvitamin D. ) After being synthesized in the skin or absorbed from the gastrointestinal (GI) tract, most vitamin D is bound to specific carrier proteins in the blood (vitamin D–binding protein [DBP] and albumin) and transported to the liver. In the liver, vitamin D is hydroxylated by the enzyme 25-hydroxylase to become 25(OH)D. 25(OH)D is the major circulating form of vitamin D. note:25-hydroxyvitamin D =calcidiol,=25OHD From the liver, 25(OH)D is transported to the kidneys via the same carrier proteins as above. 25(OH)D is hydroxylated by the enzyme 1α-hydroxylase, which is located in the mitochondria of proximal tubules of the kidney and 1,25 dihydroxyvitamin D (1,25(OH)2 D) is formed. The synthesis of 1,25(OH)2 D is tightly regulated by PTH, serum calcium, serum phosphate, and fibroblast-like growth factor 23 (FGF-23). Increased levels of PTH and hypophosphatemia stimulate the enzyme 1α-hydroxylase and, subsequently, the synthesis of 1,25(OH)2 D. FGF-23 is a circulating hormone synthesized by osteocytes and osteoblasts. 1,25(OH)2 D and phosphate intake stimulates the synthesis of FGF-23, which, in turn, inhibits 1,25(OH)2 D production, reduces the expression of renal sodium–phosphate transporters, and activates the metabolizing of active 1,25(OH)2 D to the inactive metabolite 24,25(OH)2 D.
We know that the Calcium is the most abundant mineral in the human body. The average adult body contains in total approximately 1 kg of calcium of which 99% r in the skeleton in the form of calcium phosphate salts. PTH has a rapid effect (occurring within minutes), whereby it stimulates osteoblasts to pump Ca++ ions out of the fluid surrounding the bone (which has a higher Ca++ concentration) and into the ECF. Over a longer time course, PTH stimulates bone resorption. Although PTH stimulates bone resorption, it is actually the osteoblasts that express PTH receptors. PTH stimulation of osteoblasts causes them to express a signaling molecule that activates osteoclasts. Note: Osteoblasts are bone-forming cells.Osteoclasts are bone-resorbing cells ("-clast" means to break; osteoclasts break down bone). PTH stimulates the generation of new osteoclasts (osteoclastogenesis). When they are stimulated by PTH, osteoblasts up-regulate expression of RANKL, which binds to RANK, activating signaling pathways that promote osteoclast differentiation and survival. Osteoblasts also express a secreted factor called osteoprotegerin. As its name implies, osteoprotegerin "protects bone" by preventing bone resorption. Osteoprotegerin works as a decoy receptor for RANKL: it binds RANKL and therefore prevents binding to RANK and stimulation of osteoclastogenesis. The ratio of osteoprotegerin:RANKL produced by osteoblasts will determine the extent of bone resorption. Note: Estrogen upregulate osteoprotegerin
PTH has two important effects on the kidney that work to increase [Ca++]ECF. First, it decreases the loss of Ca++ ions in the urine by stimulating Ca++ reabsorption. As well as stimulating Ca++ reabsorption, PTH also inhibits phosphate reabsorption in the kidney. The other key effect of PTH on the kidney is to stimulate production of 1,25(OH)2D, the active form of vitamin D. A precursor (known specifically as vitamin D3 or cholecalciferol)
Calcium has several main functions in the body. Calcium acts structurally as supporting material in bones as calcium phosphate. Calcium is also involved in cellular signalling pathways. Intracellular calcium functions as a second messenger in the secretion of many hormones and neurotransmitters. For instance, the influx of calcium into the neuron causes the release of Acetylcholine from pre-synaptic terminals into the neural synapse. Calcium also acts as an intracellular permeation regulator and mediator of muscle contraction. Calcium acts in the contraction of muscles by removing the Triosephosphate isomerase (TPI) subunit from Myosin heads, which has ATPase activity. Calcium also acts as an enzyme cofactor for some clotting factors (enzymes) in the coagulation cascade. Note: low ionized calcium in the extracellular fluid which results in increased permeability to sodium ions and results in hyperexcitability and seizure The body regulates calcium through the parathyroid hormone (PTH) and vitamin D, and, to a lesser extent, calcitonin. Calcium homeostasis refers to the regulation of the concentration of calcium ions in the extracellular fluid [Ca++]ECF. This parameter is tightly controlled because the calcium ions have a stabilizing effect on voltage-gated ion channels. For instance, when [Ca++]ECF is too low (hypocalcemia), voltage-gated ion channels start opening spontaneously, causing nerve and muscle cells to become hyperactive. The syndrome of involuntary muscle spasms due to low [Ca++]ECF is called hypocalcemic tetany. Conversely, when [Ca++]ECF is too high (hypercalcemia), voltage-gated ion channels don't open as easily, and there is depressed nervous system function. Another problem of hypercalcemia is that calcium can combine with phosphate ions, forming deposits of calcium phosphate(stones) in blood vessels and in the kidneys. The two most important hormones for maintaining calcium levels in the body are parathyroid hormone (PTH) and 1,25(OH)2D (the active form of vitamin D). The major regulator is PTH, which is part of a negative feedback loop to maintain [Ca++]ECF . PTH secretion is stimulated by hypocalcemia, and it works through three mechanisms to increase Ca++ levels:
Parathyroid hormone (PTH) plays a key role in the regulation of calcium and phosphate homeostasis and vitamin D metabolism. The four parathyroid glands lie behind the lobes of the thyroid. The parathyroid chief cells respond directly to changes in calcium concentrations When serum ionised calcium levels fall, PTH secretion rises.
Lithium may induce increased calcium reabsorbtion within the loop of Henle. Concurrently, lithium can alter feedback mechanisms within the parathyroid gland, impeding the suppression of PTH normally produced by hypercalcemia. Patients receiving chronic lithium therapy often develop mild hypercalcemia, most likely due to increased secretion of PTH due to an increase in the set point at which calcium suppresses PTH release. Thiazide diuretics lower urinary calcium excretion, an effect that is useful in the treatment of patients with hypercalciuria and recurrent calcium nephrolithiasis Familial hypocalciuric hypercalcemia: mutation of calcium sensing receptor Chronic granulomatous disease : Activation of extrarenal 1 alpha-hydroxylase (increased calcitriol) :increase calcium Hypercalcemia is a rare complication of pheochromocytoma. It can be due to concurrent hyperparathyroidism (in MEN, type II) or to the pheochromocytoma itself The hypercalcemia in the latter patients appears to be due to tumoral production of PTH-related protein. milk-alkali syndrome, also called Burnett's syndrome in honor of Charles Hoyt Burnett (1913–1967), the American physician who first described it, is characterized by hypercalcemia caused by repeated ingestion of calcium and absorbable alkali (such as calcium carbonate, or milk and sodium bicarbonate). If untreated, milk-alkali syndrome may lead to metastatic calcification and renal failure. Hypervitaminosis D — High serum concentrations of either 25-hydroxyvitamin D (calcidiol) or 1,25-dihydroxyvitamin D (calcitriol) can cause hypercalcemia by increasing calcium absorption and bone resorption. Thyrotoxicosis: direct effect of thyroid hormone primarily on bone metabolism Adrenal insufficiency: decrease cortisol leads to hypercalcemia by increasing renal reabsorption of ca Rhabdomyolysis and acute renal failure — Hypercalcemia has been described during the diuretic phase of acute renal failure, most often in patients with rhabdomyolysis Hypercalcemia in this setting is primarily due to the mobilization of calcium that had been deposited in the injured muscle. Etc note: Metastatic calcification is deposition of calcium salts in otherwise normal tissue, because of elevated serum levels of calcium, which can occur because of deranged metabolism as well as increased absorption or decreased excretion of calcium and related minerals, as seen in hyperparathyroidism. In contrast, Dystrophic calcification (DC) is the calcification occurring in degenerated or necrotic tissue, as in hyalinized scars, degenerated foci in leiomyomas, and caseous nodules., though blood levels of calcium remain normal. Hypercalcemia causes acute pancreatitis by pancreatic secretory block, intracellular zymogen accumulation, and acinar cell injury. Acute pancreatitis is sometimes associated with tetany and hypocalcemia. It is caused primarily by precipitation of calcium soaps in the abdominal cavity, but glucagon-stimulated calcitonin release and decreased PTH secretion may play a role. When the pancreas is damaged, free fatty acids are generated by the action of pancreatic lipase. Insoluble calcium salts are present in the pancreas, and the free fatty acids avidly chelate the salts, resulting in calcium deposition in the retroperitoneum.
Though the 50 percent pt with primary hyperparathyroidism are asymptomatic and many have non-specific symptoms ..but still the classical symptoms are described as'bones, stones and abdominal groans'. In others, symptoms may go unrecognised until patients present with renal calculi (5% of first stone formers and 15% of recurrent stone formers have primary hyperparathyroidism; . Hypertension is common in hyperparathyroidism. Parathyroid tumours are almost never palpable. Hypercalcemia causes acute pancreatitis by pancreatic secretory block, intracellular zymogen accumulation, and acinar cell injury Bathmotropic (derived from the Greek word "bathmos", meaning step or threshold) refers to modification of the degree of excitability (threshold of excitation). The neuromuscular symptoms of hypercalcemia are caused by a negative bathmotropic effect due to the increased interaction of calcium with sodium channels. Since calcium blocks sodium channels and inhibits depolarization of nerve and muscle fibers, increased calcium raises the threshold for depolarization. There is a general mnemonic for remembering the effects of hypercalcaemia: "Stones, Bones, Groans, Thrones and Psychiatric Overtones“ Symptoms are more common at high calcium blood values (12.0 mg/dL or 3 mmol/l). Severe hypercalcaemia (above 15–16 mg/dL or 3.75–4 mmol/l) is considered a medical emergency: at these levels, coma and cardiac arrest can result. Hypocalcaemia causes the opposite[clarify] – the high levels of calcium ions decrease neuronal excitability, which leads to hypotonicity of smooth and striated muscle. This explains the fatigue, muscle weakness, low tone and sluggish reflexes in muscle groups. In the gut this causes constipation. The sluggish nerves also explain drowsiness, confusion, hallucinations, stupor and / or coma.
Usually caused by a benign tumor on the parathyroid gland. Surgical removal of tumor is confirmed using intraoperative PTH. Cause of hypocalcemia since the thyroid gland is sometimes damaged during surgery and unable to produce PTH.2 High levels of calcium caused by bone metastasis that destroy the bone and release calcium into the bloodstream.3 Renal patients often have low circulating calcium levels which cause PTH levels to rise. Dietary calcium supplements help the PTH levels return to normal. Persistently elevated PTH levels in renal patients can lead to bone disease, causing muscle pain, bone deformity and increased incidence of fracture.1 Corrected calcium (mg/dL) = measured total Ca (mg/dL) + 0.8 (4.0 - serum albumin [g/dL]), where 4.0 represents the average albumin level in g/dL.
one of the most common causes of non-PTH-mediated hypercalcemia. DX : confirmed by demonstrating an elevated serum concentration of PTH-related protein (PTHrp) , which is the primary mediator of hypercalcemia in most cases . However, this assay is usually not necessary for diagnosis since most patients have clinically apparent malignancy. Levels of PTH and 1,25-dihydroxyvitamin D (calcitriol) are usually appropriately suppressed in these patients
Mild hypercalcemia — Patients with asymptomatic or mildly symptomatic hypercalcemia (calcium <12 mg/dL [3 mmol/L]) do not require immediate treatment. However, they should be advised to avoid factors that can aggravate hypercalcemia, including thiazide diuretics and lithium carbonate therapy, volume depletion, prolonged bed rest or inactivity, and a high calcium diet (>1000 mg/day). Adequate hydration (at least six to eight glasses of water per day) is recommended to minimize the risk of nephrolithiasis. Additional therapy depends mostly upon the cause of the hypercalcemia. Moderate hypercalcemia — Asymptomatic or mildly symptomatic individuals with chronic moderate hypercalcemia (calcium between 12 and 14 mg/dL [3 to 3.5 mmol/L]) may not require immediate therapy. However, they should follow the same precautions described above for mild hypercalcemia. It is important to note that an acute rise to these concentrations may cause marked changes in sensorium, which requires more aggressive therapy. In these patients, we typically treat with saline hydration and bisphosphonates, as described for severe hypercalcemia (below). Severe hypercalcemia — Patients with calcium >14 mg/dL (3.5 mmol/L) require more aggressive therapy. The acute therapy of such patients consists of a three-pronged approach [1,2,11]:
Volume expansion with isotonic saline at an initial rate of 200 to 300 mL/hour that is then adjusted to maintain the urine output at 100 to 150 mL/hour. In the absence of renal failure or heart failure, loop diuretic therapy to directly increase calcium excretion is not recommended because of potential complications and the availability of drugs that inhibit bone resorption, which is primarily responsible for the hypercalcemia. Administration of salmon calcitonin (4 international units/kg) and repeat measurement of serum calcium in several hours. If a hypocalcemic response is noted, then the patient is calcitonin-sensitive and the calcitonin can be repeated every 6 to 12 hours (4 to 8 international units/kg). We typically administer calcitonin (along with a bisphosphonate) in patients with calcium >14 mg/dL who are also symptomatic. The concurrent administration of zoledronic acid (4 mg IV over 15 minutes) or pamidronate (60 to 90 mg over two hours), preferably zoledronic acid, because it is superior to pamidronate in reversing hypercalcemia related to malignancy. The administration of calcitonin plus saline should result in substantial reduction in serum calcium concentrations within 12 to 48 hours. The bisphosphonate will be effective by the second to fourth day, thereby maintaining control of the hypercalcemia. Additional, more aggressive measures are necessary in the rare patient with very severe, symptomatic hypercalcemia. Hemodialysis should be considered, in addition to the above treatments, in patients who have serum calcium concentrations in the range of 18 to 20 mg/dL (4.5 to 5 mmol/L) and neurologic symptoms but a stable circulation. Hyperparathyroidism is the most common outpatient cause of mild hypercalcemia. The treatment is typically directed at correcting the hyperparathyroidism or monitoring for complications of primary hyperparathyroidism. Patients with lymphoma, sarcoidosis or other granulomatous causes of hypercalcemia have enhanced intestinal calcium absorption due to increased endogenous calcitriol production. The major modalities of therapy are a low calcium diet, corticosteroids, and treatment of the underlying disease. Biphosphonates are osteoclasts killers ..increase apoptosis
Hypoparathyroidism is one ofthe common cause of hypocalcemia and often develops because of surgery in the central neck requiring radical resection of head and neck cancers. The hypocalcemia may be with vitamin D deficiency. Autoimmune hypoparathyroidism is seen as an isolated defect or as part of polyglandular autoimmune syndrome type I in association with adrenal insufficiency and mucocutaneous candidiasis. Most of these patients have autoantibodies directed against the calcium-sensing receptor. Congenital causes of hypocalcemia include activating mutations of calcium-sensing receptor, which has reset the calcium–parathyroid hormone (PTH) relation to a lower serum calcium level. Finally, some cases are associated with hypoplasia or aplasia of the parathyroid glands; the best known is DiGeorge syndrome.2 Pseudohypoparathyroidism is a group of disorders with postreceptor resistance to PTH. One classic variant is Albright's hereditary osteodystrophy, associated with low stature, round facies, short digits, and mental retardation. Hypomagnesemia induces PTH resistance and also affects PTH production. Severe hypermagnesemia (>6 mg/dL) can lead to hypocalcemia by inhibiting PTH secretion. Vitamin D deficiency leads to hypocalcemia when associated with decreased dietary calcium intake. The low calcium level stimulates PTH secretion (secondary hyperparathyroidism), leading to hypophosphatemia. Acute pancreatitis precipitates calcium as a soap in the abdomen, causing hypocalcemia. Hungry bone syndrome is hypocalcemia after surgery for hyperparathyroidism (HPT) in patients with severe prolonged disease (secondary or tertiary HPT in renal failure). Serum calcium is rapidly deposited into the bone. Hungry bone syndrome is rarely seen after correction of longstanding metabolic acidosis or after thyroidectomy for hyperthyroidism. Several medications (e.g., ethylenediaminetetraacetic acid [EDTA], citrate present in transfused blood, lactate, foscarnet) chelate calcium in the circulation, sometimes producing hypocalcemia in which ionized calcium is decreased, cohereas total calcium may be normal. Extensive osteoblastic skeletal metastases (prostate and breast cancers) may also cause hypocalcemia. Chemotherapy, including cisplatin, 5-fluorouracil, and leucovorin, causes hypocalcemia mediated through hypomagnesemia. Patients with sepsis demonstrate hypocalcemia usually associated with hypoalbuminemia.
An increase in pH, alkalosis, promotes increased protein binding, which decreases free calcium levels. Hypocalcaemia may also develop as a result of magnesium depletion and should be considered in patients with malabsorption, on diuretic therapy or with a history of alcohol excess. Magnesium deficiency causes hypocalcaemia by impairing the ability of the parathyroid glands to secrete PTH (resulting in PTH concentrations that are low or inappropriately in the normal range) and may also impair the actions of PTH on bone and kidney. Conversely, ionised calcium may be low in the face of normal total serum calcium in patients with alkalosis: for example, as a result of hyperventilation. Metabolic alkalosis:It may also cause low blood calcium levels. As the blood pH increases, blood transport proteins, such as albumin, become more ionized into anions. This causes the free calcium present in blood to bind more strongly with albumin. If severe, it may causetetany.
Mild hypocalcaemia is often asymptomatic but, with more profound reductions in serum calcium, tetany can occur. This is characterised by muscle spasms due to increased excitability of peripheral nerves. Children are more liable to develop tetany than adults and present with a characteristic triad of carpopedal spasm, stridor and convulsions. In carpopedal spasm, the hands adopt a characteristic position with flexion of the metacarpophalangeal joints of the fingers and adduction of the thumb ('main d'accoucheur'). Pedal spasm can also occur but is less frequent. Stridor is caused by spasm of the glottis. Latent tetany may be detected by eliciting Trousseau's sign; inflation of a sphygmomanometer cuff on the upper arm to more than the systolic blood pressure is followed by carpal spasm within 3 minutes. Less specific is Chvostek's sign, in which tapping over the branches of the facial nerve as they emerge from the parotid gland produces twitching of the facial muscles. Hypocalcaemia can cause papilloedema and prolongation of the ECG QT interval, which may predispose to ventricular arrhythmias. Prolonged hypocalcaemia and hyperphosphataemia (as in hypoparathyroidism) may cause calcification of the basal ganglia, grand mal epilepsy, psychosis and cataracts. Hypocalcaemia associated with hypophosphataemia, as in vitamin D deficiency, causes rickets in children and osteomalacia in adults
For those with milder symptoms of neuromuscular irritability (paresthesias) and corrected serum calcium concentrations greater than 7.5 mg/dL (1.9 mmol/L), initial treatment with oral calcium supplementation is sufficient. They can be treated initially with 1500 to 2000 mg of elemental calcium given as calcium carbonate or calcium citrate daily, in divided doses. If symptoms do not improve with oral supplementation, intravenous calcium infusion is required.
The prevalence of primary hyperparathyroidism is about 1 in 800 and it is 2-3 times more common in women than men; 90% of patients are over 50 years of age. Primary hyperparathyroidism is caused by autonomous secretion of PTH, usually by a single parathyroid adenoma . It also occurs in the familial MEN syndromes or when there is nodular hyperplasia or multiple adenomas . It should be distinguished from secondary hyperparathyroidism, in which there is a physiological increase in PTH secretion to compensate for prolonged hypocalcaemia (such as in vitamin D deficiency, ), and tertiary hyperparathyroidism, in which continuous stimulation of the parathyroids over a prolonged period of time results in adenoma formation and autonomous PTH secretion which is most commonly seen in individuals with advanced chronic kidney disease. Parathyroid hormone (PTH, also known as parathormone) is a small protein that takes part in the control of calcium and phosphate homeostasis, as well as bone physiology. Parathyroid hormone has effects antagonistic to those of calcitonin. Calcium: PTH increases blood calcium levels by stimulating osteoclasts to break down bone and release calcium. PTH also increases gastrointestinal calcium absorption by activating vitamin D, and promotes calcium conservation (reabsorption) by the kidneys. Phosphate: PTH is the major regulator of serum phosphate concentrations via actions on the kidney. It is an inhibitor of proximal tubular reabsorption of phosphorus. Through activation of vitamin D the absorption of Phosphate is increased. When secondary hyperparathyroidism is corrected and the parathyroid glands remain hyperfunctioning, it becomes tertiary hyperparathyroidism.
The term multiple endocrine neoplasia (MEN) includes several distinct syndromes featuring tumors of endocrine glands, each with its own characteristic pattern. In some cases, the tumors are malignant, in others, benign. The term multiple endocrine neoplasia is used when two or more endocrine tumor types, known to occur in a single patient . The term "multiple endocrine neoplasia" was introduced in 1968.
Osteitis fibrosa results from increased bone resorption by osteoclasts with fibrous replacement in the lacunae. This may present as bone pain and tenderness, fracture and deformity. Chondrocalcinosis can occur due to deposition of calcium pyrophosphate crystals within articular cartilage. It typically affects the menisci at the knees and can result in secondary degenerative arthritis .
Skeletal X-rays are usually normal in mild primary hyperparathyroidism, but in patients with advanced disease characteristic changes are observed. In the early stages there is demineralisation, with subperiosteal erosions and terminal resorption in the phalanges. A 'pepper-pot' appearance may be seen on lateral X-rays of the skull. Reduced bone mineral density, resulting in either osteopenia or osteoporosis, is now the most common skeletal manifestation of hyperparathyroidism. assessment by DEXA scan In nephrocalcinosis, scattered opacities may be visible within the renal outline. There may be soft tissue calcification in arterial walls, soft tissues of the hands and the cornea.
DEXA stands for "dual energy X-ray absorptiometry". This type of scan is also often known as DXA, or "dual X-ray absorptiometry". It's also sometimes referred to as a bone density scan or a bone densitometry scan.
The most common cause of hypoparathyroidism is damage to the parathyroid glands (or their blood supply) during thyroid surgery, although this complication is only permanent in 1% of thyroidectomies. Transient hypocalcaemia develops in 10% of patients 12-36 hours following subtotal thyroidectomy for Graves' disease. Rarely, hypoparathyroidism can occur as a result of infiltration of the glands, e.g. in haemochromatosis and Wilson's disease.
The disorder is characterized by a lack of responsiveness to PTH, resulting in low serum calcium, high serum phosphate, and appropriately high serum parathyroid hormone. Individuals with Albright’s hereditary osteodystrophy have short stature, characteristically shortened fourth and fifth metacarpals, rounded facies, and often mild mental retardation. the kidney responds as if parathyroid hormone were absent. The PTH receptor itself is normal, but there are defective post-receptor mechanisms due to mutations
Persistent hypoparathyroidism and pseudohypoparathyroidism are treated with oral calcium salts and vitamin D analogues, either 1α-hydroxycholecalciferol (alfacalcidol) or 1,25-dihydroxycholecalciferol (calcitriol). This therapy needs careful monitoring because of the risks of iatrogenic hypercalcaemia, hypercalciuria and nephrocalcinosis. Recombinant PTH is available as subcutaneous injection therapy for osteoporosis.
Disorders of the parathyroid glands
Disorders of the parathyroid
Pratap Sagar Tiwari , MBBS MD
1α-hydroxylase Ca absorption
PTH Effects on Bone
↑Ca into ECF
PTH Effects on Kidney
• ↓the loss of Ca++ ions
in the urine by
• inhibits phosphate
• stimulate production of
Endocrine Regulation of [Ca++]ECF
1. PTH stimulates the release of Ca++ from
bone, in part by stimulating bone
2. PTH decreases urinary loss of Ca++ by
stimulating Ca++ reabsorption.
3. PTH indirectly
stimulates Ca++ absorption in the small
intestine by stimulating synthesis of
1,25(OH)2D in the kidney.
• Parathyroid hormone (PTH) plays a key role in
the regulation of calcium and phosphate
homeostasis and vitamin D metabolism.
• The four parathyroid glands lie behind the
lobes of the thyroid. The parathyroid chief
cells respond directly to changes in calcium
concentrations When serum ionised calcium
levels fall, PTH secretion rises.
With normal or elevated (i.e. inappropriate) PTH levels
• Primary or tertiary hyperparathyroidism
• Lithium-induced hyperparathyroidism
• Familial hypocalciuric hypercalcaemia , MEN
With low (i.e. suppressed) PTH levels
• Malignancy (e.g. lung, breast, renal, ovarian, colonic and
thyroid carcinoma, lymphoma, multiple myeloma)
• Elevated 1,25(OH)2 vitamin D (vitamin D intoxication,
sarcoidosis, HIV, other granulomatous disease)
• Thyrotoxicosis , pheochromocytoma
• Paget's disease with immobilisation
• Milk-alkali syndrome
• Thiazide , Lithium, theophylline
• Glucocorticoid deficiency
• The classic symptoms are described as'bones,
stones and abdominal groans'.
• Polyuria and polydipsia, renal colic, lethargy,
anorexia, nausea, dyspepsia and peptic
ulceration, constipation, depression, drowsiness
and impaired cognition.
• Patients with malignant hypercalcaemia can have
a rapid onset of symptoms.
• A family history of hypercalcaemia raises the
possibility of FHH or MEN .
Disease Ca PTH
Hyperparathyroidism High High
Hypoparathyroidism low Low
Hypercalcemia of malignancy
• one of the most common causes of non-PTH-mediated
• DX : confirmed by demonstrating an ↑serum
concentration of PTH-related protein (PTHrp) .
• Levels of PTH and 1,25-dihydroxyvitamin D
(calcitriol) are usually appropriately
suppressed in these patients.
• Mild /mod hypercalcemia : asymptomatic or
mildly symptomatic hypercalcemia (Ca <12
mg/dL do not require immediate Rx. However
maintain adequate hydration and avoid
factors that aggravate .
• Severe hypercalcemia : Patients with Ca >14
mg/dL require more aggressive Rx.
• Volume expansion with isotonic saline at an
initial rate of 200-300 mL/hr then adjusted to
maintain the UO at 100-150 mL/hour.
• If malignancy: zoledronic acid or pamidronate
• Correct hyperparathyroidism if present
• Hypocalcaemia is much less common than
• The most common cause of hypocalcaemia is
a low serum albumin with normal ionised
Differential diagnosis of
• Hypocalcemic tetany : This is characterised by
muscle spasms due to increased excitability of
• Triad of carpopedal spasm, stridor and
• Trousseau's sign; inflation of a bp cuff on the
upper arm to >the SBP is f/b carpal spasm within
• Chvostek's sign: tapping over the branches of the
facial nerve produces twitching of the facial
• Milder symptoms of neuromuscular irritability
(paresthesias) and corrected S. Ca >7.5 mg/dL
: initial Rx with oral Ca supplementation.
• 1500-2000 mg of elemental Ca given as
calcium carbonate or calcium citrate/d, in
• If symptoms do not improve with oral
supplementation, iv Ca infusion is required.
Management of severe
• 10-20mL 10% ca gluconate i.v. over 10-20 min
• Continuous i.v. infusion may be required for
several hrs (equivalent of 10 mL 10% calcium
• Cardiac monitoring is recommended .
• If Mg deficiency :50 mmol Mgcl i.v. over 24 hrs
Type Serum Ca PTH
Primary Raised Not suppressed
Single adenoma (90%)
Multiple adenomas (4%)
Secondary Low raised
Chronic renal failure
Tertiary Raised Not suppressed
Multiple endocrine neoplasia
Features MEN1 MEN2A MEN2B
Alias: Wermer S Sipple S
Pancreatic tumors ++
Pituitary adenoma ++
Medullary thyroid ca +++ ++
Pheochromocytoma + +
Mucosal neuroma +++
• Features of Hypercalcemia
• Osteitis fibrosa: results from increased bone
resorption by osteoclasts with fibrous
• Chondrocalcinosis :due to deposition of Ca
pyrophosphate crystals within articular
• In the early stages there is demineralisation, with
subperiosteal erosions and terminal resorption in the
• A 'pepper-pot' appearance :lateral X-rays of the skull.
• Reduced bone mineral density, resulting in either
osteopenia or osteoporosis. And is assessed by DEXA
• In nephrocalcinosis, scattered opacities within the
• There may be soft tissue calcification in arterial walls,
soft tissues of the hands and the cornea.
• The diagnosis can be confirmed by finding a
raised PTH level in the presence of
hypercalcaemia, provided that FHH is
• Parathyroid scanning by 99mTc-sestamibi
scintigraphy or ultrasound examination to
localise an adenoma and allow a targeted
• Post op vit D and Calcium supplements
according to lab values.
• Treatment of Hypercalcemia
• The MC cause is damage to the parathyroid
glands (or their bld supply) during thyroid Sx.
• Rarely, hypoparathyroidism can occur as a
result of infiltration of the glands, e.g. in
haemochromatosis and Wilson's disease.
• The disorder is characterized by a lack of
responsiveness to PTH, resulting in ↓ Ca, ↑Po4,
and appropriately ↑ PTH.
• Individuals with Albright’s hereditary
osteodystrophy have short stature, shortened 4th
& 5th metacarpals, rounded facies, and often
mild mental retardation.
• The kidney responds as if PTH were absent. The
PTH receptor itself is normal, but there are
defective post-receptor mechanisms due to
Management of hypoparathyroidism
• Persistent hypoparathyroidism and
pseudohypoparathyroidism are Rx with oral
calcium salts and vitamin D analogues, either
1α-hydroxycholecalciferol (alfacalcidol) or
• Recombinant PTH is available as SC injection
therapy for osteoporosis.
End of slides
• Davidson’s Principles & practice of Medicine.
• Uptodate 20.3