Cara in d training manual

CARA IN D TRAINING MANUAL

Table of Contents Parathyroid Glands...............................................................................................................3 Calcitonin.............................................................................................................................5 Vitamin D.............................................................................................................................9 Forms..................................................................................................................................10 Biochemistry......................................................................................................................11 Production in the skin.........................................................................................................11 Synthesis Mechanism.........................................................................................................13 Mechanism of action..........................................................................................................14 Deficiency..........................................................................................................................15 Emiology........................................................................................................................16 Presentation....................................................................................................................17 Diagnosis........................................................................................................................17 General characteristics...................................................................................................18 Clinical features..............................................................................................................18 Biochemical findings......................................................................................................18 Causes.............................................................................................................................18 People at risk of low vitamin D levels...............................................................................19 ............................................................................................................................................20 Vitamin D3 Cholecalciferol...............................................................................................21 Properties ...........................................................................................................................21 Forms..................................................................................................................................21 Metabolism.........................................................................................................................22 Regulation of metabolism..................................................................................................22 2

Parathyroid Glands The parathyroid glands are small endocrine glands in the neck that produce parathyroid hormone. Humans have four parathyroid glands, which are usually located behind the thyroid gland, and, in rare cases, within the thyroid gland or in the chest. Parathyroid glands control the amount of calcium in the blood and within the bones. The sole function of the parathyroid glands is to maintain the body's calcium level within a very narrow range, so that the nervous and muscular systems can function properly. When blood calcium levels drop below a certain point, calcium-sensing receptors in the parathyroid gland are activated to release hormone into the blood. 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. 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 uptake by the kidneys. 3

— Single most important hormone in the control of blood [Ca2+]. — Stimulated by decreased blood [Ca2+]. — Promotes rise in blood [Ca2+] by acting on bones, kidney and intestines. — Promotes formation of 1,25 vitamin D3. 4

Calcitonin Calcitonin is a 32-amino acid linear polypeptide hormone that is produced in humans primarily by the parafollicular (also known as C-cells) of the thyroid, The hormone participates in calcium (Ca2+) and phosphorus metabolism. In many ways, calcitonin counteracts parathyroid hormone (PTH). To be specific, calcitonin affects blood Ca2+ levels in three ways: • Inhibits Ca2+ absorption by the intestines • Inhibits osteoclast activity in bones • Inhibits Ca2+ and phosphate reabsorption by the kidney tubules Its actions, in a broad sense, are: • Bone mineral metabolism: - Protect against Ca2+ loss from skeleton during periods of Ca2+ stress such as pregnancy and lactation • Serum calcium level regulation - Prevent postprandial hypercalcemia resulting from absorption of Ca2+ from foods during a meal - Vitamin D regulation • A satiety hormone: - Inhibit food intake in rats and monkeys - May have CNS action involving the regulation of feeding and appetite 5

— Works with PTH and 1,25 vitamin D3 to regulate blood [Ca2+]. — Stimulated by increased plasma [Ca2+]. — Inhibits the activity of osteoclasts. — Stimulates urinary excretion of Ca2+ and P043- by inhibiting reabsorption. — Physiological significance in adults is questionable. 6

Vitamin D Vitamin D is a group of fat-soluble prohormones, the two major forms of which are vitamin D2 (or ergocalciferol) and vitamin D3 (or cholecalciferol). The term vitamin D also refers to metabolites and other analogues of these substances. Vitamin D3 is produced in skin exposed to sunlight, specifically ultraviolet B radiation. Vitamin D plays an important role in the maintenance of organ systems. • Vitamin D regulates the calcium and phosphorus levels in the blood by promoting their absorption from food in the intestines, and by promoting re-absorption of calcium in the kidneys, which enables normal mineralization of bone and prevents hypocalcemic tetany. It is also needed for bone growth and bone remodeling by osteoblasts and osteoclasts. • In the absence of vitamin K or with drugs (particularly blood thinners) that interfere with Vitamin K metabolism, Vitamin D can promote soft tissue calcification. • It inhibits parathyroid hormone secretion from the parathyroid gland. • Vitamin D affects the immune system by promoting phagocytosis, anti- tumor activity, and immunomodulatory functions. Vitamin D deficiency can result from inadequate intake coupled with inadequate sunlight exposure, disorders that limit its absorption, conditions that impair conversion of vitamin D into active metabolites, such as liver or kidney disorders, or, rarely, by a number of hereditary disorders. Deficiency results in impaired bone mineralization, and leads to bone softening diseases, rickets in children and osteomalacia in adults, and possibly contributes to osteoporosis. However, sunlight exposure, to avoid deficiency, carries other risks, including skin cancer; this risk is avoided with dietary absorption, either through diet or as a dietary supplement.

Forms Several forms (vitamers) of vitamin D have been discovered. The two major forms are vitamin D2 or ergocalciferol, and vitamin D3 or cholecalciferol. These are known collectively as calciferol. Chemically, the various forms of vitamin D are secosteroids; i.e., steroids in which one of the bonds in the steroid rings is broken.[7] The structural difference between vitamin D2 and vitamin D3 is in their side chains. The side chain of D2 contains a double bond between carbons 22 and 23, and a methyl group on carbon 24. Vitamin D2 is derived from fungal and plant sources, and is not produced by the human body. Vitamin D3 is derived from animal sources and is made in the skin when 7-dehydrocholesterol reacts with UVB ultraviolet light at wavelengths between 270–300 nm, with peak synthesis occurring between 295-297 nm. These wavelengths are present in sunlight when the UV index is greater than 3. At this solar elevation, which occurs daily within the tropics, daily during the spring and summer seasons in temperate regions, and almost never within the arctic circles, adequate amounts of vitamin D3 can be made in the skin after only ten to fifteen minutes of sun exposure at least two times per week to the face, arms, hands, or back without sunscreen. With longer exposure to UVB rays, an equilibrium is achieved in the skin, and the vitamin simply degrades as fast as it is generated. In humans, D3 is as effective as D2 at increasing the levels of vitamin D hormone in circulation, although others state that D3 is more effective than D2. However, in some species, such as rats, vitamin D2 is more effective than D3. Both vitamin D2 and D3 are used for human nutritional supplementation, and pharmaceutical forms include calcitriol (1alpha, 25-dihydroxycholecalciferol), doxercalciferol and calcipotriene. 10

Biochemistry Vitamin D is a prohormone, meaning that it has no hormone activity itself, but is converted to the active hormone 1,25-D through a tightly regulated synthesis mechanism. Production of vitamin D in nature always appears to require the presence of some UV light; even vitamin D in foodstuffs is ultimately derived from organisms, from mushrooms to animals, which are not able to synthesize it except through the action of sunlight at some point in the synthetic chain. For example, fish contain vitamin D only because they ultimately exist on calories from ocean algae which synthesize vitamin D in shallow waters from the action of solar UV. Production in the skin The skin consists of two primary layers: the inner layer called the dermis, composed largely of connective tissue, and the outer, thinner epidermis. The epidermis consists of five strata; from outer to inner they are: the stratum corneum, stratum lucidum, stratum granulosum, stratum spinosum, and stratum basale. Vitamin D3 is produced photochemically in the skin from 7-dehydrocholesterol. The highest concentrations of 7-dehydrocholesterol are found in the epidermal layer of skin, specifically in the stratum basale and stratum spinosum. The production of pre-vitamin D3 is therefore greatest in these two layers, whereas production in the other layers is less. Synthesis in the skin involves UVB radiation which effectively penetrates only the epidermal layers of skin. While 7-Dehydrocholesterol absorbs UV light at wavelengths between 270–300 nm, optimal synthesis occurs in a narrow band of UVB spectra between 295-300 nm. Peak isomerization is found at 297 nm. This narrow segment is sometimes referred to as D-UV. The two most important 11

factors that govern the generation of pre-vitamin D3 are the quantity (intensity) and quality (appropriate wavelength) of the UVB irradiation reaching the 7- dehydrocholesterol deep in the stratum basale and stratum spinosum. A critical determinant of vitamin D3 production in the skin is the presence and concentration of melanin. Melanin functions as a light filter in the skin, and therefore the concentration of melanin in the skin is related to the ability of UVB light to penetrate the epidermal strata and reach the 7-dehydrocholesterol- containing stratum basale and stratum spinosum. Under normal circumstances, ample quantities of 7-dehydrocholesterol (about 25-50 µg/cm² of skin) are available in the stratum spinosum and stratum basale of human skin to meet the body's vitamin D requirements, and melanin content does not alter the amount of vitamin D that can be produced. Thus, individuals with higher skin melanin content will simply require more time in sunlight to produce the same amount of vitamin D as individuals with lower melanin content. As noted below, the amount of time an individual requires to produce a given amount of Vitamin D may also depend upon the person's distance from the equator and on the season of the year. 12

Synthesis Mechanism 1. Vitamin D3 is synthesized from 7-dehydrocholesterol, a derivative of cholesterol, which is then photolyzed by ultraviolet light in 6-electron conrotatory electrocyclic reaction. The product is pre-vitamin D3. 2. Pre-vitamin D3 then spontaneously isomerizes to Vitamin D3 3. Whether it is made in the skin or ingested, vitamin D3 (cholecalciferol) is then hydroxylated in the liver to 25-hydroxycholecalciferol (25(OH)D3 or calcidiol) by the enzyme 25-hydroxylase produced by hepatocytes, and stored until it is needed. 13

4. 25-hydroxycholecalciferol is further hydroxylated in the kidneys by the enzyme 1α-hydroxylase, into two dihydroxylated metabolites, the main biologically active hormone 1,25-dihydroxycholecalciferol (1,25(OH)2D3 or calcitriol) and 24R,25(OH)2D3. This conversion occurs in a tightly regulated fashion, with renal 1α-hydroxylase being stimulated by either parathyroid hormone or hypophosphatemia. Calcitriol is represented below right (hydroxylated Carbon 1 is on the lower ring at right, hydroxylated Carbon 25 is at the upper right end). Mechanism of action Once vitamin D is produced in the skin or consumed in food, it is converted in the liver and kidney to form 1,25 dihydroxyvitamin D, (1,25(OH)2D) the physiologically active form of vitamin D (when "D" is used without a subscript it refers to either D2 or D3). This metabolically active form of vitamin D is known as calcitriol. Following this conversion, calcitriol is released into the circulation, and by binding to a carrier protein in the plasma, vitamin D binding protein (VDBP), it is transported to various target organs. The hormonally active form of vitamin D mediates its biological effects by binding to the vitamin D receptor (VDR), which is principally located in the nuclei of target cells. The binding of calcitriol to the VDR is involved in calcium absorption in the intestine. 14

The Vitamin D receptor belongs to the nuclear receptor superfamily of steroid/thyroid hormone receptors, and VDR are expressed by cells in most organs, including the brain, heart, skin, gonads, prostate, and breast. VDR activation in the intestine, bone, kidney, and parathyroid gland cells leads to the maintenance of calcium and phosphorus levels in the blood (with the assistance of parathyroid hormone and calcitonin) and to the maintenance of bone content. The VDR is known to be involved in cell proliferation, differentiation. Vitamin D also affects the immune system, and VDR are expressed in several white blood cells including monocytes and activated T and B cells. Deficiency Deficiency of vitamin D can result from a number of factors including: inadequate intake coupled with inadequate sunlight exposure, disorders that limit its absorption, conditions that impair conversion of vitamin D into active metabolites, such as liver or kidney disorders and body characteristics such as skin color and body fat. Rarely deficiency can result from a number of hereditary disorders. Deficiency results in impaired bone mineralization, and leads to bone softening diseases including: • Rickets, a childhood disease characterized by impeded growth, and deformity, of the long bones. 15

Rickets is a softening of bones in children potentially leading to fractures and deformity. Rickets is among the most frequent childhood diseases in many developing countries. The predominant cause is a vitamin D deficiency, but lack of adequate calcium in the diet may also lead to rickets (cases of severe diarrhea and vomiting may be the cause of the deficiency). Although it can occur in adults, the majority of cases occur in children suffering from severe malnutrition, usually resulting from famine or starvation during the early stages of childhood. Osteomalacia is the term used to describe a similar condition occurring in adults, generally due to a deficiency of vitamin D.[1] The origin of the word "rickets" is probably from the Old English dialect word 'wrickken', to twist. The Greek derived word "rachitis" (meaning "inflammation of the spine") was later adopted as the scientific term for rickets, due chiefly to the words' similarity in sound. In many languages it is known as "English disease". Emiology Those at higher risk for developing rickets include: • Breast-fed infants whose mothers are not exposed to sunlight • Breast-fed infants who are not exposed to sunlight • Individuals not consuming fortified milk, such as those who are lactose intolerant Individuals with red hair have been speculated to have a decreased risk for rickets due to their greater production of vitamin D in sunlight. It should also be noted that new-born infants can even have rickets at birth, if the mother had low vitamin D levels during pregnancy, often referred to as Congenital Rickets 16

Presentation Signs and symptoms of rickets include: • Bone pain or tenderness • dental problems • muscle weakness (rickety myopathy or "floppy baby syndrome" or "slinky baby" (where the baby is floppy or slinky like)) • increased tendency for fractures (easily broken bones), especially greenstick fractures • Skeletal deformity o Toddlers: Bowed legs (genu varum) o Older children: Knock-knees (genu valgum) or "windswept knees" o Cranial, spinal, and pelvic deformities • Growth disturbance • Hypocalcemia (low level of calcium in the blood), and • Tetany (uncontrolled muscle spasms all over the body). • Craniotabes (soft skull) • Costochondral swelling (aka "rickety rosary" or "rachitic rosary") • Harrison's groove • Double malleoli sign due to metaphyseal hyperplasia • Widening of wrist raises early suspicion, it is due to metaphysial cartilage hyperplasia. An X-ray or radiograph of an advanced sufferer from rickets tends to present in a classic way: bow legs (outward curve of long bone of the legs) and a deformed chest. Changes in the skull also occur causing a distinctive "square headed" appearance. These deformities persist into adult life if not treated. Long-term consequences include permanent bends or disfiguration of the long bones, and a curved back. Diagnosis A doctor may diagnose rickets by: • Blood tests: o Serum calcium may show low levels of calcium, serum phosphorus may be low, and serum alkaline phosphatase may be high. • Arterial blood gases may reveal metabolic acidosis • X-rays of affected bones may show loss of calcium from bones or changes in the shape or structure of the bones. • Bone biopsy is rarely performed but will confirm rickets. 17

• Osteomalacia, a bone-thinning disorder that occurs exclusively in adults and is characterized by proximal muscle weakness and bone fragility. Osteomalacia is the general term for the softening of the bones due to defective bone mineralization. Osteomalacia in children is known as rickets, and because of this, osteomalacia is often restricted to the milder, adult form of the disease. It may show signs as diffuse body pains, muscle weakness, and fragility of the bones. A common cause of the disease is a deficiency in Vitamin D, Osteoporosis is a disease of bone that leads to an increased risk of fracture. In osteoporosis General characteristics the bone mineral density (BMD) is reduced, bone microarchitecture is disrupted, and the amount and variety of non-collagenous proteins in bone is altered. Osteoporosis is defined by the World Osteomalacia in the adult is most commonly found in mineral density 2.5 standard deviations below Health Organization (WHO) in women as a bone confined, dark-skinned, or diet-disbalanced subjects. Many mass (20-year-old healthy female average) as measured by osteoporosis, but the two peak bone of the effects of the disease overlap with the more common DXA; the term diseases are significantly different. Osteomalacia is specifically a defect in [1] Osteoporosis isthe protein "established osteoporosis" includes the presence of a fragility fracture. mineralization of most framework known as osteoid.menopause, when it is called postmenopausalby lack in vitamin D.may common in women after This defective mineralization is mainly caused osteoporosis, but also develop in men, and may occur in anyone in the presence of particular hormonal disorders Osteomalacia chronic diseases or as osteo refers to bone, and malacia means softness. In the past, and other is derived from Greek: a result of medications, specifically glucocorticoids, when the the disease was also steroid- ormalacosteon and its Latin-derived equivalent, mollities ossium. its disease is called known as glucocorticoid-induced osteoporosis (SIOP or GIOP). Given influence on the risk of fragility fracture, osteoporosis may significantly affect life expectancy and quality of life. Clinical features Osteomalacia in adults starts insidiously as aches and pains in the lumbar (lower back) region and thighs, spreading later to the arms and ribs. Pain is non-radiating, symmetrical, and accompanied by tenderness in the involved bones. Proximal muscles are weak, and there is difficulty in climbing up stairs and getting up from a squatting position. Due to demineralization bones become less rigid, physical signs include deformities like triradiate pelvis and lordosis. The patient has a typical "waddling gait". However that physical signs may derive from a previous osteomalacia state, since bones don't regain the original shape after they're deformed. Pathologic fractures due to weight bearing may develop. Most of the time, the only alleged symptom is chronic fatigue and bone aches are not spontaneous but only revealed by pressure or shocks. Biochemical findings Biochemical features are similar to rickets.The major fact is a collapsed vitamin D rate in blood or serum. The major findings are 1 The serum calcium is low 2 urinary calcium is low 3 serum phosphate is low except in cases of renal osteodystrophy 4 serum alkaline phosphate is high the technetium bone scan will show increased activity Causes The causes of adult osteomalacia are varied. • Insufficient sunlight exposure, especially in dark-skinned subjects • Insufficient nutritional quantities or faulty metabolism of vitamin D or phosphorus • Renal tubular acidosis • Malnutrition during pregnancy • Malabsorption syndrome • Chronic renal failure • Tumor induced osteomalacia • Therapy with Fumaderm • Celiac disease 18

Vitamin D malnutrition may also be linked to an increased susceptibility to several chronic diseases such as high blood pressure, tuberculosis, cancer, periodontal disease, multiple sclerosis, chronic pain, seasonal affective disorder, peripheral artery disease and several autoimmune diseases including type 1 diabetes. There is an association between low vitamin D levels and Parkinson's disease, but whether Parkinson's causes low vitamin D levels, or whether low vitamin D levels play a role in the pathogenesis of Parkinson's disease has not been established. People at risk of low vitamin D levels — Older people in residential care — Older people admitted to hospital — Patients with hip fracture — Dark-skinned men and women (particularly if veiled) — Mothers of infants with rickets — People unable to obtain regular sun exposure 19

Vitamin D3 Cholecalciferol Cholecalciferol is a form of Vitamin D, also called vitamin D3 or calciol. It is structurally similar to steroids such as testosterone, cholesterol, and cortisol One gram of pure vitamin D3 is 40 000 000 (40x106) IU, or, in other words, one IU is 0.025 μg. Properties Molecular formula C27H44O Molar Mass 384.64 g/mol Appearance White, needle-like crystals Melting point 83–86 °C Forms Vitamin D3 has several forms: • Cholecalciferol, (sometimes called calciol) which is an inactive, unhydroxylated form of vitamin D3) • Calcidiol (also called 25-hydroxyvitamin D3), which is the form measured in the blood to assess vitamin D status • Calcitriol (also called 1,25-dihydroxyvitamin D3), which is the active form of D3. 21

Metabolism 7-Dehydrocholesterol is the precursor of vitamin D3 and forms cholecalciferol only after being exposed to solar UV radiation. Cholecalciferol is then hydroxylated in the liver to become calcidiol (25- hydroxyvitamin D3). Next, calcidiol is again hydroxylated, this time in the kidney, and becomes calcitriol (1,25-dihydroxyvitamin D3). Calcitriol is the most active hormone form of vitamin D3. Regulation of metabolism • Cholecalciferol is synthesized in the skin from 7-dehydrocholesterol under the action of ultraviolet B light. It reaches an equilibrium after several minutes depending of several factors including conditions of sunlight (latitude, season, cloud cover, altitude), age of skin, and color of skin. • Hepatic hydroxylation of cholecalciferol to calcidiol (25- hydroxycholecalciferol) is loosely regulated, if at all, and blood levels of this molecule largely reflect the amount of vitamin D3 produced in the skin or the vitamin D2 or D3 ingested. • Renal hydroxylation of calcidiol to calcitriol by 1-alpha-hydroxylase is tightly regulated (stimulated by either parathyroid hormone or hypophosphatemia) and serves as the major control point in production of the most active circulating hormone calcitriol (1,25-dihydroxyvitamin D3). 22

Cara in d training manual

by Azam Jafri on Apr 21, 2010

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