Calicium Homeostasis

2. Control of calcium homeostasis
Control of calcium homeostasis
depends on:
• Parathyroid hormone
• Vitamin D
• PTHrP
• Calcitonin
Normal serum calcium
8.6-10.5 mg/dl (2.1-2.6 mmol/L)

3. Vitamin D
The natural form of vitamin D, cholecalciferol or
vitaminD3, is formed in the skin by the action
of UV light on7-dehydrocholesterol, a
metabolite of cholesterol. Few foods contain
vitamin D naturally and skin exposure to
sunlight is the main source.
Vitamin D is converted in the liver to 25-
hydroxy vitamin D (25(OH)D), which is
further hydroxylated in the kidneys to 1,25-
dihydroxy-vitamin D (1,25 (OH)2D), the
active form of the vitamin.

4. 1,25(OH)2D activates specific intracellular
receptors which influence calcium metabolism,
bone mineralisation and tissue differentiation.
The synthetic form, ergocalciferol, or vitamin
D2, is considered to be less potent than the
endogenous D3. Recommended dietary intakes
aim to prevent rickets and osteomalacia. There
is increasing evidence that vitamin D is
important for immune and muscle function,
and may reduce falls in the elderly

6. Vitamin D deficiency
The most common cause of osteomalacia and
rickets is vitamin D deficiency, which can
result from either lack of sunlight exposure,
from which the majority of vitamin D is
derived; dietary deficiency ; or malabsorption
of vitamin D in patients with gastrointestinal
disease.

7. Clinical features
Vitamin D deficiency in children causes delayed
development, muscle hypotonia, craniotabes
(small unossified areas in membranous bones
of the skull that yield to finger pressure with a
cracking feeling), bossing of the frontal and
parietal bones and delayed anterior fontanelle
closure, enlargement of epiphyses at the lower
end of the radius, and swelling of the rib
costochondral junctions (‘rickety rosary’).

8. rickety rosary

9. Osteomalacia in adults presents insidiously. Mild
osteomalacia can be asymptomatic or present
with fractures and mimic osteoporosis. More
severe osteomalacia presents with muscle and
bone pain, general malaise and fragility
fractures. Proximal muscle weakness is
prominent and the patient may walk with a
waddling gait and struggle to climb stairs or
get out of a chair. There may be bone and
muscle tenderness on pressure and focal bone
pain can occur due to fissure fractures of the
ribs and pelvis.

10. Investigations
The diagnosis can usually be made on a
biochemical screen with measurement of
serum 25(OH)D and PTH. Typically, serum
ALP levels are raised, 25(OH)D levels are low
or undetectable, and PTH is elevated. Serum
calcium and phosphate levels may also be low
but normal values do not exclude the
diagnosis. X-rays are normal until advanced
disease, when focal radiolucent areas
(pseudofractures or Looser’s zones) may be
seen in ribs, pelvis and long bones.

11. Looser’s zones

13. Management
Osteomalacia and rickets respond promptly to treatment
with vitamin D (250–1000 μg daily), with rapid
clinical improvement, an elevation in serum
25(OH)D and a reduction in PTH. Serum ALP levels
sometimes rise initially as mineralisation of bone
increases, but eventually fall to within the reference
range as the bone disease heals. After 3–4 months,
treatment can generally be stopped or the dose of
vitamin D reduced to a maintenance level of 10–20
μg of cholecalciferol daily, except in patients with
underlying disease such as malabsorption, in whom
higher doses may be required.

14. Vitamin D3 Supplement

15. Parathyroid glands
The four parathyroid gland are located on the
posterior surface of thyroid, one on each pole
and weigh between 25 and 40 mg.

16. Action of parathyroid hormone
Parathyroid hormone (PTH) increases
calcium level by the following
mechanisms:
1. Increase calcium release from the
bones.
2. Increase calcium reabsorption by the
kidney.
3. Increase calcium absorption from the
GIT through stimulation of 1,25
cholecalciferol synthesis by the
kidney.

17. • More than 99% of total body calcium is
in bone. Prolonged exposure of bone to
high levels of PTH is associated with
increased osteoclastic activity and new
bone formation, but the net effect is to
cause bone loss with mobilisation of
calcium into the extracellular fluid. In
contrast, pulsatile release of PTH causes
net bone gain, an effect that is exploited
therapeutically in the treatment of
osteoporosis

19. Parathyroid hormone related
peptide (PTHrP)
• Many cell types produce PTHrP,
including brain, pancreas, heart, lung,
mammary tissue, placenta,
endothelial cells, and smooth muscle.
• PTHrP slows the differentiation of
chondrocytes and bind the same
receptors of PTH.
• PTHrP is responsible for most cases
of hypercalcemia of malignancy.

20. Calcitonin
• Calcitonin is a hypocalcemic peptide hormone that in
several mammalian species acts as the physiologic
antagonist to PTH.
• Calcitonin is secreted from the parafollicular C cells
of the thyroid gland. Although it is a useful tumour
marker in medullary carcinoma of thyroid and can be
given therapeutically in Paget’s disease of bone, its
release from the thyroid is of no clinical relevance to
calcium homeostasis in humans, and its medical use
as an adjunctive treatment in severe hypercalcemia.

21. Hypercalcaemia
• Hypercalcaemia is one of the most common
biochemical abnormalities and is often
detected during routine biochemical analysis in
asymptomatic patients. However, it can present
with chronic symptoms, as described below,
and occasionally as an acute emergency with
severe hypercalcaemia and dehydration.

23. • Primary hyperparathyroidism and malignant
hypercalcaemia are by far the most common.
Familial hypocalciuric hypercalcaemia (FHH)
is a rare but important cause that needs
differentiation from primary
hyperparathyroidism (HPT). Lithium may
cause hyperparathyroidism by reducing the
sensitivity of the calciumsensing receptor.

24. Clinical features of Hypercalcemia
• Mild hypercalcemia usually asymptomatic.
• Moderate to severe hypercalcemia (11.5 to
13.5 mg/dL) presented with nausea,
vomiting, constipation, polyuria, fatigue,
depression, renal stones and arrhythmias.
• If hypercalcemia is detected in otherwise
asymptomatic patient then it is usually due
to hyperparathyroidism, while in case of
malignancy the patient suffers from
symptoms of the tumor before that of
Hypercalcemia.

27. Primary Hyperparathyroidism
• 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. 50 %
of cases are asymptomatic and may remain so
for years.
• In addition to common features of
Hypercalcemia, other specific feature of
hyperparathyroidism is osteitis fibrosa cystica
which is characterized by resorption of
phalangeal tufts on X-rays.

28. Osteitis Fibrosa Cystica

30. ‘pepper-pot’ appearance may be seen on lateral X-rays of the
skull

31. Nephrocalcinosis

32. 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 or predispose
to attacks of acute pseudogout.

34. Diagnosis and treatment
• Diagnosis is confirmed by
radioimmunoassay of PTH.
• Affected gland is diagnosed by
preoperative 99mTc-sestamibi
scintigraphy or by intraoperative selective
venous sampling.
• Treatment is by surgical removal of the
affected glands.
• Oral cinacalcet hydrochloride is the first
in a new class of therapeutic agents.

35. Treatment of severe hypercalcemia
• 0.9% normal saline: Most patients with acute
hypercalcemia are volume-depleted, and
expansion of the extracellular space will
enhance calcium excretion.
• Loop diuretics: Only when the patients are
euvolemic, a loop diuretic such as furosemide
can be added to enhance calciuresis.
• Bisphosphonates: iv pamidronate inhibit
osteoclastic bone resorption and are
particularly effective in hypercalcemia of
malignancy.
• Calcitonin: Calcitonin inhibits osteoclast
function and causes rapid fall of serum
calcium.

36. Hypocalcemia

37. Causes of transient
Hypocalcemia
1. Acute pancreatitis.
2. Extensive transfusion with
citrated blood.
3. Rhabdomyolysis
4. Hysterical hyperventilation
(low ionized calcium)

38. Causes of chronic Hypocalcemia
1. Chronic kidney disease
2. Hypoparathyroidism :(hereditary [PAS] and acquired)
3. Pseudohypoparathyroidism : (post-receptor resistance
to PTH)
4. Vitamin D deficiency :(nutritional and malabsorption)
5. Hypoalbuminemia (Adjust calcium upwards by 0.02
mmol/L (0.08 mg/dL) for each 1 g/L reduction in
albumin below 40 g/L.). If albumin concentrations
are significantly low, as in severe acute illness and
other chronic illness such as liver cirrhosis, this
correction is less accurate and measurement of
ionised calcium is needed.

39. Hypomagnesemia
6. Hypocalcaemia may also develop as a result of
magnesium depletion and should be considered in
patients with malabsorption, those on diuretic or
proton pump inhibitor therapy, and/or those 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
reference range) and may also impair the actions of
PTH on bone and kidney.

40. Clinical features of Hypocalcemia
• Mild hypocalcemia is often
asymptomatic.
• Neuromuscular irritability (tetany)
include muscle spasms, carpopedal
spasm, and, in extreme cases, laryngeal
spasm and convulsions.
• Chvostek's or Trousseau's sign can be
used to confirm latent tetany.
• Mental changes include irritability,
depression, and psychosis.
• Cardiac complications include prolonged
QT interval in ECG and arrhythmias.

41. • 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.

42. Carpal spasm
(‘main d’accoucheur’)

43. Chvostek's
sign

44. Trousseau's sign
(systolic pressure for 3 min)

46. Treatment of Hypocalcemia
• Acute symptomatic hypocalcemia treated
with intravenous infusion of 10-20 ml
10% calcium gluconate over 10 -20 min.
• Chronic hypocalcemia treated with oral
vitamin D and calcium supplement.
• In CRF and hypoparathyroidism use end
hormone 1,25 dihydroxyvitamin D3 in
the form of calcitriol (0.25 to 1 µg/d).

47. • Recombinant PTH ( Teriparatide )is available
as subcutaneous injection therapy for
osteoporosis and, although not currently
licensed, has been used in hypoparathyroidism.

48. Multiple endocrine neoplasias(MEN)
• Multiple endocrine neoplasias
(MEN) are rare autosomal dominant
syndromes characterised by
hyperplasia and formation of
adenomas or malignant tumours in
multiple glands.
• They fall into four groups

51. The MEN syndromes should be considered in all
patients with two or more endocrine tumours
and in patients with solitary tumours who
report other endocrine tumours in their family.
• Individuals who carry mutations associated
with MEN should be entered into a
surveillance programm.

52. MEN 1 (Wermer's syndrome)
• Involving the Parathyroid glands,
the Pancreatic islets, and the
anterior Pituitary.
• Nonendocrine manifestations
include lipomas and facial
angiofibromas.

53. MEN 1 (Wermer's syndrome)
• Parathyroid tumor is most common tumor
(95–100% )presents with hypercalcemia.
• The pancreatic tumors occur in 50% of
patients. Pancreas involved with multiple
adenomas secreting gastrin, insulin, or
glucagon. The most common presentation is
Zollinger-Ellison syndrome, a peptic ulcer
disease associated with gastrin-producing
tumors.
• Pituitary tumors occur in about one third of
patients. Prolactinoma is the most common
tumors.

54. MEN 2
–MEN 2a (Sipple's syndrome) :
manifests with medullary carcinoma of
the thyroid (MCT),
pheochromocytoma, and, less
commonly, hyperparathyroidism.
–MEN 2b: in addition to MCT and
pheochromocytoma; there are mucosal
neuromas of the tongue, lips, eyelids,
and gastrointestinal tract and a
marfanoid habitus.

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