M-K 03 Metabolisme Kalsium

Metabolisme Kalsium Hafiz Suwoto

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).

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.

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 ionized calsium akan lebih rendah.

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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 apical membrane dari enterocytes di usus halus.

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 parathyroid (PTH).

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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.

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 kalsium darah.

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.

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++.

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.

• 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.

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.

extracellular space T tubules: invaginations of (T tubule lumen) voltage-gated muscle plasma membrane. Ca++ channel

Voltage-gated Ca++ channels in the T tubule membrane interact with ryanodine receptors in the ++ Ca ryanodine closely apposed SR receptor membrane.

cytosol SR lumen

Activation of voltage-gated Ca++ channels, by an action potential in the T tubule, leads to opening of ryanodinesensitive 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.

Multiple biological functions of calcium • Cell signalling • Neural transmission • Muscle function • Blood coagulation • Enzymatic co-factor • Membrane and cytoskeletal functions • Secretion • Biomineralization

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

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

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

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

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Other dietary factors regulating calcium absorption – Lactose – Phosphorus

Calcium Absorption (0.4-1.5 g/d) • Primarily in duodenum – 15-20% absorption

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Adaptative changes – – – –

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low dietary calcium growth (150 mg/d) pregnancy (100 mg/d) lactation (300 mg/d)

Fecal excretion

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

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

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Two general mechanisms – Active - transcellular – Passive - paracellular

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Proximal tubule and Loop of Henle reabsorption – Most of filtered load – Mostly passive – Inhibited by furosemide

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Distal tubule reabsorption – 10% of filtered load – Regulated (homeostatic) • • • •

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stimulated by PTH inhibited by CT vitamin D has small stimulatory effect stimulated by thiazides

Urinary excretion – 50 - 250 mg/day – 0.5 - 1% filtered load

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

Disorders of Calcium and Phosphate Metabolism

Outline 1. Review of calcium and phosphate metabolism 2. Abnormalities of calcium balance 3. Abnormalities of phosphate balance 4. Example cases

Major Mediators of Calcium and Phosphate Balance • Parathyroid hormone (PTH) • Calcitriol (active form of vitamin D3)

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 ↓ serum phosphate

Regulation of PTH Low serum [Ca+2]  Increased PTH secretion High serum [Ca+2]  Decreased PTH secretion

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 ↑ serum phosphate

Regulation of Calcitriol

Overview of Calcium-Phosphate Regulation

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: [Ca+2]Corrected = [Ca+2]Measured + [ 0.8 (4 – Albumin) ]

Overview of Biochemical Homeostasis

Overview of Calcium Balance

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

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 Vitamin D deficiency / low calcitriol

Overview of Phosphate Balance

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 Tumor lysis syndrome

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

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

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 Phosphate – 0.7 mg/dL Albumin – 1.8 g/dL Creatinine – 1.3 mg/dL CK – 3500 U/L

(normal ~ 8.5-10.2 mg/dL) (normal ~ 2.0-4.3 mg/dL) (normal ~ 3.5-5.0 g/dL)

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 Creatinine – 2.8 mg/dL (baseline creatinine = 1.1)

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 Potassium – 4.1 meq/L Magnesium – 2.3 mg/dL Calcium (total) – 6.9 mg/dL Phosphate – 4.4 mg/dL Albumin – 4.2 g/dL Creatinine – 0.8 mg/dL

Urine tox. screen – Negative Urine pregnancy - Negative

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