M-K 03 Metabolisme Kalsium

(1)

Metabolisme Kalsium

(2)

Metabolisme Kalsium

• Kalsium adalah mineral terbanyak ditemukan

dalam tubuh manusia.

• Rata-rata seorang dewasa mengandung sekitar

1 kg, 99% diantaranya terdapat pada rangka.

• Cairan ekstrasel (ECF) mengandung sekitar

22.5 mmol, dimana sekitar 9 mmol terdapat

dalam

serum

.

• Lebih kurang 500 mmol kalsium mengalami

pertukaran diantara tulang rangka dengan ECF

selama waktu 24 jam. (Marshall, 1995).

(3)

Nilai Normal :

• Serum Kalsium mempunyai pengaturan yang

ketat dengan nilai normal total calcium 2.2-2.6

mmol/L (9-10.5 mg/dL) dan normal ionized

calcium 1.1-1.4 mmol/L (4.5-5.6 mg/dL). Kadar

kalsium darah ini diatur secara ketat terutama

kadar ionized calcium.

• Jumlah kalsium total berbeda sesuai dengan

kadar

albumin

, suatu protein dimana kalsium

dapat terikat.

• Efek biologis kalsium ditentukan oleh jumlah

ionized calcium, dan bukan oleh kadar total

kalsium.

Ionized

calcium diketahui ternyata tidak

berbeda dan paralel dengan kadar albumin, hal

ini berguna untuk pengukuran ion kalsium, bila

kadar albumin tidak normal tentu ditemukan

kelainan metabolisme kalsium meskipun kadar

kalsium total di plasma normal.

(4)

Kadar kalsium yang telah dikoreksi :

• Bila ditemukan kelainan pada kadar albumin, kadar kalsium dapat ditentukan melalui suatu proses koreksi.

• Hal ini digunakan untuk menentukan kadar sebenarnya dari total kalsium yang disebabkan oleh perubahan pada ikatan kalsium-albumin. Hal ini memberikan perkiraan berapa

seharusnya kadar total kalsium bila kadar albumin berada dalam kisaran normal.

– Kadar kalsium yang telah dikoreksi (mg/dl) = kadar total kalsium yang terukur (mg/dl) + 0.8 (4.0 – kadar serum albumin terukur (g/dl))

– nilai 4.0 mempresentasikan nilai rata albumin.

• Bila terdapat hypoalbuminemia (kadar albumin < normal) maka kadar kalsium yang telah dikoreksi akan lebih besar dari pada kadar total kalsium terukur akan tetapi kadar

(5)

Sumber kalsium :

• Lebih kurang 25

mmol

kalsium dikonsumsi oleh

manusia pada diet yang normal.

• Bila diet mempunyai kadar susu yang rendah

termasuk bahan-bahan yang mengandung kalsium

tinggi maka asupan dari diet akan rendah juga.

• Sekitar 40% (10 mmol) diabsorpsi di lambung dan 5

mmol akan keluar dari tubuh bersama feces.

Sisanya akan diabsorpsi di usus halus.

• Vitamin D

merupakan ko-faktor penting pada proses

“

intestinal absorption

of calcium”, karena dapat

meningkatkan jumlah “

calcium binding proteins

”,

yang berperan pada absorpsi melalui

(6)

Ekskresi :

• Ginjal

memfiltrasi sekitar 250 mmol per hari

dan meresorbpsi kembali sekitar 245 mmol,

sehingga kehilangan melalui urin hanya sekitar

5 mmol/l.

• Ginjal juga berperan memproses vitamin D

menjadi

kalsitriol (1,25-bisOH kolekalsiferol)

,

yang merupakan bentuk aktif yang berperan

membantu absorpsi di usus halus.

• Kedua proses diatas distimulasi oleh

hormon

(7)

Peran tulang pada metabolisme kalsium :

• Tulang berperan sebagai cadangan penyimpan

kalsium terbesar karena 99% total kalsium tubuh

terdapat di tulang. Dalam keadaan normal sekitar 5

mmol mengalami pertukaran di tulang.

• Calcium dapat dibebaskan dari tulang oleh

hormon

parathyroid

.

• Calcitonin berperan menstimulasi masuknya

kalsium ke dalam tulang meskipun prosesnya

sendiri tidak dipengaruhi oleh calcitonin.

• Rendahnya asupan kalsium dalam diet dapat

menjadi faktor risiko pada perkembangan

osteoporosis.

• Dengan mempertahankan keseimbangan kalsium

proses osteoporosis dapat dicegah.

(8)

Organ-organ pengatur :

• Organ pengatur terpenting adalah kelenjar

parathyroid. Kelenjar ini terdapat dibawah

kelenjar thyroid, dan menghasilkan hormon

parathyroid bila kadar kalsium darah

menurun.

• Sel-sel parafollicular dari kelenjar thyroid

menghasilkan calcitonin bila kadar kalsium

darah meningkat.

• Akan tetapi dalam hal ini peran PTH lebih

menentukan dalam pengaturan kadar

(9)

Kelainan yang ditemukan pada metabolisme

kalsium :

• Hypocalcemia dan hypercalcemia merupakan

kelainan yang sangat serius.

• Renal osteodystrophy dapat terjadi sebagai

konsekwensi dari chronic renal failure yang

berhubungan dengan metabolisme kalsium.

• Osteoporosis dan osteomalacia juga merupakan

kelainan yang disebabkan oleh gangguan pada

metabolisme kalsium.

(10)

Peran Kalsium sebagai pengatur

kontraksi otot :

• Untuk terjadinya kontraksi otot miosin harus

berikatan dengan actin, akan tetapi tropomyosin

yang terdapat dalam struktur filamen actin akan

memblok situs pengikatan pada protein actin

sewaktu otot berada dalam keadaan relaksasi.

• Bila kontraksi distimulasi oleh impuls saraf maka

troponin yang terdapat dalam struktur filamen

actin akan menggeser tropomiosin sehingga situs

pengikatan pada actin terbuka dan dapat mengikat

miosin.

• Perubahan pada struktur filamen actin akan

membentuk actomiosin dan kontraksi otot akan

berlangsung. Proses pembukaan situs pengikatan

ini diregulasi oleh adanya ion Ca++.

(11)

Pengaturan oleh ion kalsium berlangsung sbb:

• Bila saraf motorik memicu timbulnya potensial aksi pada sel otot akan dihasilkan suatu senyawa pencetus berupa neurotransmiter. Perbedaan potensial antara bagian luar dan dalam akan mengalami pembalikan polarisasi. Arus polarisasi yang terjadi dengan segera ditransmisikan

keseluruh serat otot oleh T tubuli dan menembus sampai ke sarcomer. Setiap T tubulus berada pada Z line.

• Sarcoplasmic reticulum sangat sensitif terhadap

perubahan polarisasi itu. Selanjutnya sisterna terminalis menjadi permeabel terhadap ion Ca++ dan akan

membebaskan ion tersebut ke sarcomer. Ca++ ion akan mengikat troponin yang selanjutnya mengikat

tropomyosin dan membuka situs pengikatan pada protein actin, dan selanjutnya akan mengikat miosin. • Begitu terikat pada actin miosin akan memecah ATP

dan membebaskan energi yang diperlukan untuk menarik filamen actin ke arah pusat sarcomer  kontraksi otot terjadi.

(12)

• Kontraksi otot ini akan terus berlanjut

selama masih terdapat ion Ca++ bebas di

dalam sarcomer.

• Bila stimulasi saraf berhenti maka

membran dari sisterna terminalis dengan

cepat akan memompakan ion Ca++ bebas

kemabali ke sisterna. Menghilangnya ion

Ca++, troponin tidak dapat lagi mengikat

tropomiosin, sehingga tropomiosin akan

kembali memblokir situs pengikatan

miosin pada protein actin  kontraksi otot

berhenti.

(13)

Ryanodine Receptor

Kanal pembebasan ion

Ca

++

pada membran

Retikulum sarkoplasmik sel otot

(SR) disebut he

ryanodine receptor

, karena reseptor ini sangat

sensitif terhadap alkaloid tumbuhan ryanodin.

Skeletal dan otot kardiak kontraksinya diaktifkan

bila ion Ca

++

dibebaskan dari lumen SR ke sitosol

melalui ryanodin reseptor.

(14)

Activation of voltage-gated Ca

++

channels, by an action

potential in the T tubule, leads to opening of

ryanodine-sensitive Ca

++

-release channels.

Ca

++

moves

from the SR lumen

to the cytosol

, passing

through the transmembrane part of the ryanodine receptor,

& then through the receptor's cytoplasmic assembly.

Ca

++ cytosol SR lumen ryanodine receptor extracellular space (T tubule lumen) voltage-gated Ca++ channel

T tubules

: invaginations of

muscle plasma membrane.

Voltage-gated

Ca

++

channels

in the T tubule

membrane interact with

ryanodine receptors

in the

closely apposed SR

(15)

Multiple biological functions of calcium

• Cell signalling

• Neural transmission

• Muscle function

• Blood coagulation

• Enzymatic co-factor

• Membrane and cytoskeletal functions

• Secretion

(16)

Distribution of Calcium

• Total body calcium- 1kg

– 99% in bone

– 1% in blood and body fluids Intracellular calcium – Cytosol – Mitochondria – Other microsomes – Regulated by "pumps"

• Blood calcium - 10mgs (8.5-10.5)/100 mls

– Non diffusible - 3.5 mgs – Diffusible - 6.5 mgs

(17)

Bone Structure (cellular and non-cellular)

• Inorganic (69%)

– Hydroxyapatite - 99%

• 3 Ca10 (PO4)6 (OH)2

• Organic (22%)

– Collagen (90%)

– Non-collagen structural proteins

• proteoglycans • sialoproteins • gla-containing proteins – α2HS-glycoprotein • Functional components • growth factors • cytokines

(18)

Blood Calcium - 10mgs/100 mls(2.5

mmoles/L)

• Non diffusible - 3.5 mgs

– Albumin bound - 2.8 – Globulin bound - 0.7

• Diffusible - 6.5 mgs

– Ionized - 5.3 – Complexed - 1.2 mgs • bicarbonate - 0.6 mgs • citrate - 0.3 mgs • phosphate - 0.2 mgs • other

– Close to saturation point

• tissue calcification • kidney stones

(19)

Diet

• Dietary calcium

– Milk and dairy products (1qt = 1gm) Dietary supplements – Other foods

• Other dietary factors regulating calcium absorption – Lactose – Phosphorus Calcium Absorption (0.4-1.5 g/d) • Primarily in duodenum – 15-20% absorption • Adaptative changes

– low dietary calcium – growth (150 mg/d) – pregnancy (100 mg/d) – lactation (300 mg/d) • Fecal excretion

(20)

Mechanisms of GI Calcium Absorption

• Vitamin D dependent

• Duodenum > jejunum > ileum

• Active transport across cells

– calcium binding proteins (e.g., calbindins)

– calcium regulating membranomes

• Ion exchangers

• Passive diffusion

(21)

Urinary Calcium

• Daily filtered load – 10 gm (diffusible) – 99% reabsorbed

• Two general mechanisms – Active - transcellular

– Passive - paracellular

• Proximal tubule and Loop of Henle reabsorption – Most of filtered load

– Mostly passive

– Inhibited by furosemide • Distal tubule reabsorption

– 10% of filtered load

– Regulated (homeostatic)

• stimulated by PTH • inhibited by CT

• vitamin D has small stimulatory effect • stimulated by thiazides

• Urinary excretion – 50 - 250 mg/day

(22)

Regulation of Urinary Calcium

• Hormonal - tubular reabsorption

– PTH - decreases excretion (clearance) – CT - increases excretion (calciuretic) – 1,25(OH)2D - decreases excretion

• Diet

– Little effect – Logarithmic

• Other factors

– Sodium - increases excretion

– Phosphate - decreases excretion – Diuretics - thiazides vs loop

• thiazides - inhibit excretion

• furosemide - stimulate excretion

Other Routes of Excretion

• Perspiration • Lactation

(23)

Disorders of Calcium and

Phosphate Metabolism

(24)

Outline

1. Review of calcium and phosphate

metabolism

2. Abnormalities of calcium balance

3. Abnormalities of phosphate balance

4. Example cases

(25)

Major Mediators of Calcium and

Phosphate Balance

• Parathyroid hormone (PTH)

(26)

Role of PTH

• Stimulates renal reabsorption of calcium

• Inhibits renal reabsorption of phosphate

• Stimulates bone resorption

• Inhibits bone formation and mineralization

• Stimulates synthesis of calcitriol

Net effect of PTH



↑

serum calcium

↓

(27)

Regulation of PTH

Low serum [Ca

+2

]  Increased PTH secretion

(28)

Role of Calcitriol

• Stimulates GI absorption of both calcium

and phosphate

• Stimulates renal reabsorption of both

calcium and phosphate

• Stimulates bone resorption

Net effect of calcitriol



↑

serum calcium

↑

(29)

(30)

(31)

Different Forms of Calcium

At any one time, most of the calcium in the body exists as the mineral hydroxyapatite, Ca10(PO4)6(OH)2.

Calcium in the plasma:

45% in ionized form (the physiologically active form) 45% bound to proteins (predominantly albumin)

10% complexed with anions (citrate, sulfate, phosphate)

To estimate the physiologic levels of ionized calcium in states of hypoalbuminemia:

(32)

(33)

(34)

Etiologi Hypercalcemia

Increased GI Absorption

Milk-alkali syndrome Elevated calcitriol

Vitamin D excess

Excessive dietary intake Granuomatous diseases Elevated PTH

Hypophosphatemia Increased Loss From Bone

Increased net bone resorption Elevated PTH

Hyperparathyroidism Malignancy

Osteolytic metastases PTHrP secreting tumor Increased bone turnover

Paget’s disease of bone Hyperthyroidism

Decreased Bone Mineralization Elevated PTH

Aluminum toxicity

Decreased Urinary Excretion Thiazide diuretics Elevated calcitriol Elevated PTH

(35)

Etiologi Hypocalcemia

Decreased GI Absorption

Poor dietary intake of calcium Impaired absorption of calcium

Vitamin D deficiency

Poor dietary intake of vitamin D Malabsorption syndromes

Decreased conversion of vit. D to calcitriol Liver failure

Renal failure Low PTH

Hyperphosphatemia

Decreased Bone Resorption/Increased Mineralization Low PTH (aka hypoparathyroidism)

PTH resistance (aka pseudohypoparathyroidism) Vitamin D deficiency / low calcitriol

Hungry bones syndrome Osteoblastic metastases

Increased Urinary Excretion Low PTH

s/p thyroidectomy s/p I131_treatment

Autoimmune hypoparathyroidism PTH resistance

(36)

(37)

Etiologi Hyperphosphatemia

Increased GI Intake

Fleet’s Phospho-Soda Decreased Urinary Excretion

Renal Failure

Low PTH (hypoparathyroidism) s/p thyroidectomy

s/p I131 treatment for Graves disease of thyroid cancer

Autoimmune hypoparathyroidism Cell Lysis

Rhabdomyolysis

(38)

Etiologi Hypophosphatemia

Decreased GI Absorption

Decreased dietary intake (rare in isolation) Diarrhea / Malabsorption

Phosphate binders (calcium acetate, Al & Mg containing antacids) Decreased Bone Resorption / Increased Bone Mineralization

Vitamin D deficiency / low calcitriol Hungry bones syndrome

Osteoblastic metastases Increased Urinary Excretion

Elevated PTH (as in primary hyperparathyroidism) Vitamin D deficiency / low calcitriol

Fanconi syndrome

Internal Redistribution (due to acute stimulation of glycolysis)

Refeeding syndrome (seen in starvation, anorexia, and alcholism) During treatment for DKA

(39)

Case 1

Mrs. T is a 59 year old woman with a past medical history

significant for hypertension who comes for a routine clinic visit. She initially states that she has no symptomatic complaints, but later in the interview describes chronic fatigue and a mildly

depressed mood. Her exam is unremarkable. Labs are as follows:

Calcium (total) – 11.9 mg/dL (normal ~ 8.5-10.2 mg/dL)

Phosphate – 1.8 mg/dL (normal ~ 2.0-4.3 mg/dL)

Albumin – 3.8 g/dL (normal ~ 3.5-5.0 g/dL) PTH – 124 pg/mL (normal ~ 10-60 pg/mL) Creatinine – 1.2 mg/dL

(40)

Case 2

Mr. G is a 40 year old man with a history of alcoholism. He had not seen a doctor for 15 years before police brought him to the ER after finding him confused and disheveled behind a local convenience store. In the ER, he was thought to be confused simply due to intoxication, but was admitted for mild alcoholic hepatitis and marked malnutrition. His mental status cleared up about 8 hours after admission. During morning rounds on hospital day #2, he complained of feeling fatigued and weak. Later that day, the nurses find him seizing. The seizures stop with low dose IV diazepam. Stat labs are sent:

Sodium – 136 meq/L Potassium – 3.2 meq/L

Calcium (total) – 6.8 mg/dL (normal ~ 8.5-10.2 mg/dL) Phosphate – 0.7 mg/dL (normal ~ 2.0-4.3 mg/dL) Albumin – 1.8 g/dL (normal ~ 3.5-5.0 g/dL) Creatinine – 1.3 mg/dL

(41)

Case 3

Mr. H is a 74 year old man with a past history significant for

hypertension and COPD from smoking 2 packs per day for the last 40 years. He presented to an urgent pulmonary clinic

appointment with 2 months of increased cough and 5 days of “mild” hemoptysis. Upon further obtaining further history, he reports feeling fatigued, nauseous, and chronically thirsty for several weeks. His exam is significant for bilateral rhonchi (no change from baseline lung exam) and absent reflexes. Stat labs are ordered from clinic:

Sodium – 138 meq/L CBC, PT/PTT – WNL

Potassium – 3.7 meq/L PTH - Pending

Magnesium – 1.8 mg/dL Albumin – 2.2 g/dL

Calcium (total) – 13.1 mg/dL Phosphate – 1.3 mg/dL

(42)

Case 4

Miss L is a 16 year old woman with no significant past medical history, who is brought to the ER by her mother after she noted her to be acting bizarrely for the past several weeks. Thought to be actively psychotic, a psychiatry consult is asked to see the patient, who recommends checking routine labs:

Sodium – 142 meq/L Urine tox. screen – Negative Potassium – 4.1 meq/L Urine pregnancy - Negative Magnesium – 2.3 mg/dL

Calcium (total) – 6.9 mg/dL Phosphate – 4.4 mg/dL

Albumin – 4.2 g/dL

(43)