ENDOCRINOLOGY Lec. 7 Dr. Ali al-bayati - PowerPoint Presentation

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ENDOCRINOLOGY

Lec. 7

Dr. Ali al-bayati

Biochemistry of the Parathyroid Glands & Ca

+2

homeostasis

Calcium metabolismMost

abundant mineral in the human bodyTotal Calcium in the human body is about 1 to 1.5 kg, 99% of which

is seen in bone together with phosphate

Small amounts in soft tissue & 1% in extracellular fluid

•

Dietary Sources of calcium:• Milk is a good source for calcium• Egg, fish, cheese, beans, lentils, nuts, cabbage and vegetables are sources for calcium

Daily requirement of calcium

•

Adults = 500 mg/day

•

Children’s = 1200 mg/day

•

Pregnancy & lactation = 1500 mg/day

•

After the age of 50, tendency for osteoporosis, prevented by increased

calcium (1500 mg/day) & vitamin D (20 μg/day)

Body Distribution of Calcium

About 99% of calcium is found in bones; It exists as carbonate or phosphate of calciumAbout 0.5% in soft tissue and 0.1% in extracellular fluid

Calcium in plasma is of 3 types

Ionized or free or unbound calcium: In blood, 50% of plasma calcium is free & is metabolically active. It is required for the maintenance of nerve function, membrane permeability, muscle contraction and hormone secretion.

Bound calcium:

40% of plasma calcium is bound to protein mostly albumin. These two forms are diffusible from blood to tissuesComplexed calcium: 10% of plasma calcium is complexed with anions including bicarbonate, phosphate, lactate & citrate

Absorption• Mechanism of absorption of calcium:

Calcium is taken in the diet as calcium phosphate, carbonate & tartarate

About 40% of dietary calcium is absorbed from the gut

Absorption occurs form the first & second part of duodenum;

Absorbed

against a concentration gradient & requires energy, and a carrier protein, helped by calcium-dependent ATPase

Two

mechanisms for absorption of calcium:

•

Simple diffusion

•

An active transport -

Process

involving energy & Ca

2+

pump

•

Both processes

require 1, 25 DHCC (Calcitriol) which regulates the

synthesis of

Ca-binding proteins & transport

• Vitamin D:

Calcitriol induces the synthesis of carrier protein (Calbindin) in the intestinal epithelial cells & facilitates the absorption of calcium•

Parathyroid hormone:

It increases calcium transport from the intestinal cells by enhancing

1α-

hydroxylase activityIf intake is low, active transport

in the duodenum is increased and a larger proportion of calcium is absorbed by the active process compared with the passive Para cellular process that occurs in the jejunum and ileum

.

Vitamin D is important for the active process. Active calcium transport depends on the presence in the intestinal cell of

calbindin protein

, the biosynthesis of which is totally dependent on vitamin D.

Regulation of plasma calcium level• Dependent on the function of 3 main organs

BoneKidney

Intestine

• 3 main hormones

Calcitriol

Parathyroid hormoneCalcitonin• Also by GH, glucocorticoids, estrogens, testosterone & thyroid

Regulation of plasma calcium level by vitamin D

Role of vitamin D

on bone:

In osteoblasts of bone, calcitriol stimulates calcium uptake

for

deposition as calcium phosphatevitamin D is essential for bone formationCalcitriol along with parathyroid hormone increases the

mobilization

of

calcium and

phosphate

from the

bone,

Causes

elevation in the plasma calcium and phosphate

Role of calcitriol on kidneys

•

vitamin

D

increase level of Ca

+2

& phosphate

by

decreasing

their

excretion

&

enhancing reabsorption

Role

of calcitriol on intestine:

•

Calcitriol

increases the intestinal absorption of Ca

2+

& phosphate

•

Calcitriol

binds with a cytosolic receptor to form a calcitriol-receptor complex

•

Complex

interacts with DNA leading to the synthesis of a specific calcium

binding

protein&

This

protein

increases calcium uptake by intestine

Regulation by parathyroid hormone (PTH)

• Parathyroid hormone (PTH) is secreted by two pairs of parathyroid glands•

Parathyroid hormone (mol. wt. 95,000) is a single chain polypeptide

, containing 84 amino acids• It is

originally synthesized as prepro PTH,

which is degraded to proPTH and, finally, to active PTH• The rate of formation & secretion of PTH are promoted by low

Ca

2+

concentration

Control of Parathyroid Hormone SecretionParathyroid hormone is released in response to low extracellular concentrations of free calcium.

When calcium concentrations fall below the normal range, there is an increase in secretion of parathyroid hormone.Low levels of the hormone are secreted even when blood calcium levels are high. The parathyroid cell monitors extracellular free calcium concentration via an integral membrane protein that functions as a calcium-sensing receptor

.

Calcium itself can be thought of as a type of hormone, and the calcium sensor as its receptor

.

The calcium-sensing receptor is a member of the G protein-coupled receptor family. Activation of the calcium sensor has two major signal-transducing effects:Activation of phospholipase C, which leads to generation of the two second messengers diacylglycerol and inositol triphosphate. Inhibition of adenylate cyclase, which suppresses intracellular concentration of cAMP

The calcium sensor

is expressed in a broad range of cells, including parathyroid cells and C cells in the thyroid gland, indicating its involvement in controlling the synthesis and secretion of parathyroid hormone and calcitonin

.The calcium sensor is also expressed in several cell types in the kidney, osteoblasts, a variety of hematopoietic cells in bone marrow, and in the gastrointestinal mucosa. Strangely, it is also present in the squamous epithelial cells of the esophagus. Such a broad distribution of expression supports that concept that calcium, acting as a hormone, has direct effects on the function of many cell types.

Calcitonin• Calcitonin

is a peptide containing 32 amino acids• It is

secreted by parafolicular

cells of thyroid gland• The action of CT on calcium is antagonistic to that of PTH

•

Calcitonin promotes calcification by increasing the activity of osteoblasts• Calcitonin decreases bone resorption & increases the excretion of Ca2+ into

urine

•

Calcitonin has a decreasing influence on blood calcium

Hypercalcemia• The

serum Ca2+ level >11 mg/dl is called as Hypercalcemia

• Causes:

• Hyperparathyroidism:Decrease

in serum phosphate (due to increased renal losses) and

increase in ALP activity are found in hyperparathyroidismUrinary excretion of Ca2+ & P resulting in formation of urinary calculi

The

determination of ionized Ca

2+

(elevated to 6-9mg/dl) is useful for

the

diagnosis

of hyperparathyroidism

Clinical features of hypercalcemia

•

Neurological symptoms

such as depression, confusion, inability to

concentrate

•

Generalized muscle weakness

•

Gastrointestinal problems

such as

anorexia, abdominal pain, nausea,

vomiting & constipation

•

Renal feature

such as polyuria &

polydipsia

•

Cardiac

arrhythemias

Hypocalcemia• Decreased serum Ca

2+ < 8.8 mg/dl is called as hypocalcemia• Causes:

Hypoproteinaemia:If

albumin concentration in serum falls, total calcium is low because the

bound

fraction is decreasedHypoparathyroidism: The commonest cause is neck surgery, idiopathic or due to magnesium deficiencyVitamin

D deficiency:

May

be

due to malabsorption or an inadequate diet with little

exposure

to

sunlight;

Leads

to bone disorders,

osteomalacia

& rickets

Renal

disease

:

In

kidney diseases,

the

1, 25 DHCC (calcitriol) is not synthesized due

to impaired hydroxylation

5-

Pseudohypoparathyroidism

: PTH is secreted but there is failure of target tissue receptors to respond to the hormone

• Clinical features of hypocalcemia:

• Enhanced neuromuscular irritability

• Neurologic features such as tingling, tetany, numbness (fingers and toes),

muscle cramps

• Cardiovascular signs such as an abnormal

ECG •

Cataracts

Thank you