calcium functions and significance.pptx

Calcium-FunctionsandClinical Significance
DrAnwaarAhmed
By- Professor Namrata Chhabra (MD Biochemistry)
07/24/14 1
Institute of Food and Nutritional Sciences
PMAS-AAUR

Introduction
Calcium(Ca)is required for the:
•Muscle contraction,
•Nerve conduction,
•Hormone release, and
•Blood coagulation
•In addition, specific Calciumconcentration is
required for various other metabolicprocesses.
07/24/14
By- Professor Namrata Chhabra
(MD Biochemistry)
2
PMAS-AAUR

Sourcesof calcium
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It is an important nutrient.Thedaily
intake is approximately
1000mg/day, about the amount of
one litre ofmilk.
Widely distributed infood
substancessuch as
Milk
Cheese
Egg-yolk
Fish
Beans
Lentils
Nutsand
Cabbage
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(MD Biochemistry)
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Intestinal Absorption of calcium
Two mechanisms have been proposed-
• Simple passive diffusion
• Active transport- involving energy andcalcium
pump.
o Vitamin Dis important for the activeprocess.
o Active calcium transport depends on the
presence in the intestinal cell of calbindin
protein , the biosynthesis ofwhich is totally
dependent on vitaminD.
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(MD Biochemistry)
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PMAS-AAUR

Intestinal
absorption
Institute of Food and Nutritional Sciences PMAS-
AAUR
• 30-80% of ingested calcium isabsorbed,
primarily in the upper smallintestine.
• Absorption is related to calciumintake.
• If intake is low, active transcellular calcium
transport in the duodenum is increased anda
larger proportion of calcium is absorbed by
the active processcompared with thepassive
paracellular process that occurs in the
jejunum andileum.

Intestinal
absorption
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• Passive absorption in the jejunum and ileum
predominates when dietary calcium intake is
adequate or high.
• Calcium reaching the large intestine isabsorbed
by active and passiveprocesses.
• Usually, not more than 10%of total absorption
takes place in the large intestine, but this site
becomes nutritionally important in conditionsof
significant small bowel resection.

Intestinal
absorption
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In a balanced diet, roughly 1000 mg of Cais ingested
each day and about another 200 mg/day is secreted
into the GItract in the bile and other GIsecretions.
Depending on the concentration of circulating vitamin
D,particularly 1,25(OH)2D(1,25
Dihydroxycholecalciferol, Calcitriol, or active vitaminD,
roughly 200 to 400 mg of Cais absorbed from the
intestine eachday.
Theremaining 800 to 1000 mg appears in thestool.
Cabalance is maintained through renal Caexcretion
averaging 200 mg/day.

Factors affecting calcium absorption
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A)Factorsfavoringcalcium absorption
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An acidic pH
Presenceof sugar acids, organic acids and citricacid
High protein diet- LysineandArginine causemaximal absorption
Presenceof vitamin D
Ca: Pratio- Aratio of dietary Ca:Pnot more than 2:1 is adequate
for optimal absorption, ratio of less than 1:2 reduces absorption
State of health and intact mucosa-Ahealthy adultabsorbs about
40%of dietary calcium.
PTH(Parathormone) stimulates the activation of vitamin D,thus
indirectly increases absorption of vitaminD

Factors affecting calcium absorption
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B)Factorsinhibiting absorptionof calcium
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Alkaline pH
High fat diet- Fatty acids form calcium soapsthat can not be
absorbed
Presenceof Phytates and oxalates- Insoluble calcium saltsare
formed
Dietary fiber in excessinhibitsabsorption
Excessphosphates, magnesium and iron decrease absorption
Glucocorticoids reduce intestinal absorption ofcalcium
Calcitonin reduces calcium absorption indirectly by inhibitingthe
activation of vitaminD
Advancing ageand intestinal inflammatory disordersinhibit
absorption of calcium

Distribution of Bodycalcium
 The adult human body contains approximately 1100g (27.5mol) of
calcium.
 99%of the calcium is in bone.
 Blood calcium levels are normally 9-10.2mg/dL(2.25- 2.55mmol/L).
 Of the total amount, 50%is free ionized calcium, 9%is combined with
various anions (including bicarbonate, citrate, phosphate, lactate and
sulphate) and the remaining 41%is bound to serum proteins mainly
albumin.
 Free ionized calcium is the physiologically important component of
the total calcium.
 In plasma, the ionized calcium concentration isnormally maintained
within a tight range(1.0-1.25mmol/l).
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07/24/14
By- Professor Namrata Chhabra (MD
Biochemistry)
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PMAS-AAUR

 Both extracellular and intracellular Caconcentrations are tightly regula
by bidirectional Catransport across the plasma membrane of cells and
intracellular organelles, such asthe endoplasmic reticulum, the
sarcoplasmic reticulum of muscle cells, and themitochondria.
 Cytosolic ionized Cais maintained within the micromolar range (<1/10
of the serumconcentration).
 Despite its important intracellular roles, roughly 99%of body Cais in
bone, mainly ashydroxyapatitecrystals.
 Roughly 1%of bone Cais freely exchangeable with the ECFand, therefo
available for buffering changes in Ca balance.
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Influences on calcium concentrations
 The plasma pH and the total plasma protein concentration influence th
total calciumlevels
 Since a significant proportion of calcium in the blood is bound to
albumin, it is important to know the plasma albumin concentration
when evaluating the total plasma calcium.
 In general, 0.2mmol/L must be added to the total calcium concentrat
for each 1g/dL decrease in albumin concentration
 Ionized calcium increases with acidosis, and decreaseswith alkalosis.
 Therefore, for each 0.1 decrease in pH, ionizedcalcium rises by about
0.05mmol/L.
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Physiologicalfunctions of calcium
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1)Calciumis necessaryfor several physiological
processesincluding neuromuscular
transmission,smoothandskeletal muscle
contraction, cardiacautomaticity, nerve
function, celldivisionandmovement, and
certain oxidative processes.
2)It is also aco-factor for manystepsduring
blood coagulation.

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3) Cais also involved in the actionof other
intracellular messengers,suchascyclic
adenosine monophosphate (cAMP)and
Inositol 1,4,5-triphosphate, and thusmediates
the cellular response to numerous hormones,
including epinephrine, glucagon,ADH
(vasopressin), secretin, and cholecystokinin.

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4) Calciumbinding proteins
• Many different calcium binding proteinshave
been described, but the two with well
established functions are troponin and
calmodulin.
• Troponin is involved in muscle contraction,
whereas calmodulin causes configurational
changesto proteins and enzymeactivation.

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6) Releaseof neurotransmitters andhormones-
Intracellular calcium levels are much lower than
the extracellular, due to relative membrane
impermeability and membrane pumpsemploying
active transport.
• Calcium entry via specific channels leads to direct
effects, e.g. neurotransmitter release in neurons,
or further calcium release from intracellular
organelles, e.g. in cardiac and skeletalmuscle.

Regulation of calcium homeostasis
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Three principal hormones are involved in calcium
homeostasis
• Vitamin D,
• Parathormone and
• Calcitonin
Acting at three targetorgans,
• Intestine,
• Boneand
• Kidneys

Role of vitamin Din calcium homeosta
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•Vitamin Dis agroup of closely related sterolsproduced
by the action of ultravioletlight.
•Vitamin D3 (Cholecalciferol) is produced by the action of
sunlight and is converted to 25-hydroxycholecalciferol in
the liver.
•The25-hydroxy-cholaecalciferol is converted in the
proximal tubules of the kidneys to the more active
metabolite 1,25-hydroxy-cholaecalciferol.
•1,25-hydroxychlecalceriferol synthesis is regulated in a
feedback fashion by serum calcium andphosphate.
•Its formation is facilitated by parathyroidhormone.

Role of vitamin Din calcium homeosta
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Theactions of Vitamin Dare asfollows:
1.Enhancescalcium absorption from the
intestine
2.Facilitates calcium absorption in thekidney
3.Increasesbone calcification and
mineralization
4.In excess,mobilizes bone calciumand
phosphate

Role of Parathyroid hormone
(PTH)
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• Parathyroid hormone is alinear polypeptide
containing 84 amino acidresidues.
• It is secreted by the chief cells in the four
parathyroid glands.
• Plasmaionized calcium acts directly on the
parathyroid glands in afeedback manner to
regulate the secretion ofPTH.
• In hypercalcemia, secretion is inhibited, andthe
calcium is deposited in thebones.
• In hypocalcaemia, parathyroid hormone
secretion isstimulated.

Parathyroid glands
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Biochemistry)
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Role of Parathyroid hormone
(PTH)
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Theactions of PTHare aimed at raising serum calcium. It -
1. Increases bone resorption by activating osteoclasticactivity
2. Increases renal calcium reabsorption by the distalrenal
tubules
3. Increases renal phosphate excretion by decreasingtubule
phosphate reabsorption
4. Increases the formation of 1,25-dihydrocholecalciferolby
increasing the activity of alpha-hydroxyls in the kidney
Alarge amount of calcium is filtered in the kidneys, but 99%
of the filtered calcium is reabsorbed.About 60%is
reabsorbed in the proximal tubules and the remainder in
the ascending limb of the loop of Henle and the distal
tubule. Distal tubule absorption is regulated byparathyroid
hormone.

Regulation of calcium homeostasis
Institute of Food and Nutritional
Sciences PMAS-AAUR

Role of Calcitonin
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Calcitonin is a32 amino acid polypeptide secreted bythe
parafollicular cells in the thyroidgland.
It tends to decreaseserum calcium concentrationand, in
general, haseffects opposite to those ofPTH.
Theactions of calcitonin are asfollows:
1. Inhibits bone resorption
2. Increases renal calcium excretion
Theexact physiological role of calcitonin incalcium
homeostasis is uncertain.
Theeffects of calcitonin on bone metabolism aremuch
weaker than those of either PTHor vitaminD.

Role of Calcitonin, Calcitriol and PTH
Institute of Food and Nutritional Sciences PMAS-AAUR

Glucocorticoids and calcium homeostas
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• Glucocorticoids lower serum calcium levels by
inhibiting osteoclast formation and activity, but
over long periods they causeosteoporosis by
decreasing bone formation and increasingbone
resorption.
• They also decrease the absorption of calcium
from the intestine by an anti-vitamin Daction
and increased its renalexcretion.
• Thedecrease in serum calcium concentration
increases the secretion of parathyroidhormone,
and bone resorption isfacilitated.

Growth hormone and calcium
levels
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• Growth hormone increases calciumexcretion
in the urine
• it also increases intestinal absorptionof
calcium, and
• this effect may be greater than the effect on
excretion, with
• aresultant positive calciumbalance.

Effect of other hormones on calcium level
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• Thyroid hormones may causehypercalcemia,
hypercalciuria, and, in some instances,
osteoporosis.
• Oestrogens prevent osteoporosis, probablyby
adirect effect onosteoblasts.
• Insulin increases bone formation, and thereis
significant bone loss in untreateddiabetes.

Boneand calcium
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Thecalcium in bone exists in twoforms:
1.Areadily exchangeablepool and which is about 0.5 to 1% of
the total calcium salts and is the first line of defense against
changesin plasma calcium. It provides arapid buffering
mechanism to keep the serum calcium ion concentration in
the extracellular fluids from rising to excessive levels or falling
to very low levels under transient conditionsof excess or
hypo availability of calcium.
2.Stable Pool-Theother system is mainly concerned with
bone remodeling by the constant interplay ofbone resorption
and deposition, which accounts for 95%of boneformation.

Extracellular calcium homeostasis
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Calcium-sensingreceptor (CASR)
TheCASRplays an essential role in maintaining
calcium ion homeostasis-
• Thisreceptor is expressedin all tissues relatedto
calcium control, i.e. parathyroid glands, thyroid
C-cells,kidneys, intestines andbones.
• It hasthe ability to sensesmall changesinplasma
calcium concentration
• Thisinformation is conveyed to intracellular
signaling pathways that modify PTHsecretion or
renal calcium handling.

Calcium-sensingreceptor (C ASR)
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It is aGprotein-coupled receptor that plays anessential
part in regulation ofextracellular calcium homeostasis.

Keypoints in calcium homeostasis
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•Calcium homeostasis is regulated by
three hormones, parathyroid
hormone, vitamin Dand calcitonin.
•Parathyroid hormone increases
plasma calcium by mobilizing it from
bone, increases reabsorption from
the kidney and also increases the
formation of 1, 25
dihydrocholecalciferol.
•1,25-dihydrocholecalciferol increases
calcium absorption from the
intestine, mobilizes calcium from the
bone and increases calcium
reabsorption in the kidneys
•Calcitonin inhibits bone resorption
and increases the amount ofcalcium
in the urine, thus reducing plasma
calcium
•Thecalcium-sensing receptor (CASR)
plays an important role in regulation
of extracellular calcium.

Hypocalcaemia
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Hypocalcemiaistotal serumCaconcentration<8.8
mg/dL(< 2.20 mmol/L) in the presence of normalplasma
protein concentrations or aserum ionized Ca
concentration <4.7 mg/dL (< 1.17 mmol/L).
Causesinclude hypoparathyroidism, vitamin Ddeficiency,
and renal disease.
•Acute hypocalcaemia can also occur in the immediate
post-operative period, following removal ofthe thyroid
or parathyroidglands.
•Hypocalcaemia canoccur following rapid administration
of citrated blood or large volumes of albumin and in
alkalosis causedby hyperventilation.

Hypocalcaemia
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Other causesof hypocalcemiainclude-
• Mg depletion (can causerelative PTH
deficiency and end-organ resistance to PTH
action),
• Acute pancreatitis (when lipolytic products
released from the inflamed pancreaschelate
Ca)
• Hypoproteinemia (reduces the protein-bound
fraction of serumCa)

Hypocalcaemia
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Hungry bone syndrome-(persistent hypocalcemia and
hypophosphatemia occurring after surgical or medical
correction of moderate tosevere hyperparathyroidism
in patients in whom serum Calevels had been
supported by high bone turnover induced by greatly
elevated parathyroid hormone)
Septic shock (due to suppression of PTHrelease and
decreased conversion of 25(OH)Dto 1,25(OH)2D)
Drugsincluding anticonvulsants
(e.g., phenytoin , phenobarbital and rifampinwhich
alter vitamin Dmetabolism)

Clinical manifestations of Hypocalcaem
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•Hypocalcemia is frequently asymptomatic.
•Major clinical manifestations of hypocalcemia are
due to disturbances in cellular membranepotential,
resulting in neuromuscularirritability.
•Clinicalsignsinclude: tetany, carpopedal spasm
and laryngeal stridor.
•Sensorysymptoms consisting of paresthesiasof
the lips, tongue, fingers, andfeet
•Generalized muscle aching and spasmof facial
musculature are alsothere

Clinical manifestations of Hypocalcaem
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• Hypocalcaemia may lead to cardiac
Dysrhythmias, decreased cardiac contractility,
causing hypotension, heart failure orboth.
• Many other abnormalities may occur with
chronic hypocalcemia, suchasdry and scaly
skin, brittle nails, and coarsehair.

Clinical manifestations of Acute
Hypocalcaemia
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Biochemistry)
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Diagnosisof Hypocalcaemia
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• Estimation of ionizedCa
• Further testing with Mg, PTH,PO4,alkaline
phosphatase, and vitamin Dconcentrations in
blood and cAMPand PO4concentrations in
urine
• Electrocardiographic changesinclude
prolongation of the QTinterval.

Treatment of
Hypocalcaemia
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• IVCaGluconate for tetany
• Oral Cafor postoperativehypoparathyroidism
• Oral Caand vitamin Dfor chronic
hypocalcemia
• In patients without renal failure, vitaminDis
given asastandard oral supplement (e.g.,
Cholecalciferol 800 IUonce/day).
• Vitamin Dtherapy is not effective unless
adequate dietary or supplemental CaandPO4

Hypercalcaemia
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Hypercalcemia is total serumCa
concentration >10.4 mg/dL (> 2.60 mmol/L) or
ionized serum Ca>5.2 mg/dL (> 1.30mmol/L).
PrincipalCausesof Hypercalcemia-
Hypercalcemia usually results from excessive
bone resorption. There are many causesof
hypercalcemia

Principal CausesofHypercalcemia
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A)Cancerwith bone metastases
• Carcinoma
• Leukemia
• Lymphoma
• Multiple myeloma

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B)Immobilization
• Orthopedic casting or traction
• Paget's diseaseof bone
• Osteoporosis in theelderly
• Paraplegia or quadriplegia
• Young, growing patients

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C)Parathyroidhormoneexcess
• Parathyroid carcinoma
• Primary hyperparathyroidism
• Secondary hyperparathyroidism
D) Vitamin Toxicity
• Vitamin Atoxicity
• Vitamin Dtoxicity

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E)Other disorders/causes
• Hyperthyroidism
• Milk-alkali syndrome
• Addison's disease
• Granulomatous disorders
• Drug therapy suchasthiazides and lithium

Hypercalcemia related to
hyperparathyroidism
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Clinical manifestations of Hypercalcaem
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• In mild hypercalcemia, many patientsare
asymptomatic.
• Clinical manifestations of hypercalcemia
include constipation, anorexia, nauseaand
vomiting, abdominal pain, andileus.
• Impairment of the renal concentrating
mechanism leads to polyuria, nocturia,and
polydipsia.

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• Elevation of serum Ca>12 mg/dL (> 3.00
mmol/L) can causeemotional lability,
confusion, delirium, psychosis,stupor,and
coma.
• Hypercalcemia may causeneuromuscular
symptoms, including skeletal muscle
weakness.

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• Hypercalciuria with nephrolithiasisis
common.
• Lessoften, prolonged or severe
hypercalcemia produces reversible acuterenal
failure or irreversible renal damage due to
nephrocalcinosis (precipitation of Casalts
within the kidneyparenchyma).

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• Severehypercalcemia causesashortened
QTcinterval on ECG,and arrhythmiasmay
occur
• Hypercalcemia >18 mg/dL (> 4.50 mmol/L)
may causeshock, renal failure, anddeath.

Diagnosisof Hypercalcaemia
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• Total serum Caconcentration
• Chestx-ray, measurement of electrolytes,
BUN,creatinine, ionized Ca,PO4,alkaline
phosphatase, and serum protein
immunoelectrophoresis to determinethe
cause
• Measurement of PTHand urinary excretionof
Cawith or without PO4

Treatment of Hypercalcaemia
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There are 4 main strategies for loweringserum
Ca:
• Decreaseintestinal Caabsorption
• Increase urinary Caexcretion
• Decreasebone resorption
• RemoveexcessCathrough dialysis

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• Oral PO4
for serum Ca<11.5 mg/dL with mild
symptoms and no kidney disease
• IVsaline and diuretic (furosemide) formore
rapid correction for serum Ca<18mg/dL
• Bisphosphonates or other Ca-lowering drugs
for serum Ca<18 mg/dL and >11.5 mg/dL or
moderate symptoms

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• Hemodialysis for serum Ca>18mg/dL
• Surgicalremoval for moderate, progressive primary
hyperparathyroidism andsometimes for mild
disease
• PO4
restriction and binders and
sometimes Calcitriol for secondary
hyperparathyroidism

Summaryof calcium metabolism
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Caisrequired for the proper functioning ofmuscle contraction, nerve
conduction, hormone release, blood coagulationand for various other
metabolic processes.
Maintenance of body Castores dependson Dietary Caintake
Absorption of Cafrom the GItract RenalCa
excretion
Theregulation of both CaandPO4
balanceisgreatly influenced by
concentrations of circulating PTH,vitamin D,and,to alesserextent,
calcitonin.

 Hypocalcemia is total serum Caconcentration <8.8 mg/dL
(< 2.20 mmol/L) in the presence ofnormal plasma protein
concentrations or aserum ionized Ca concentration <4.7
mg/dL (< 1.17 mmol/L).
Causesinclude hypoparathyroidism, vitamin D
deficiency, and renal disease.
Manifestations include paresthesias, tetany, and,when
severe, seizures, encephalopathy, and heart failure.
 Diagnosis involves measurement of serum Cawith
adjustment for serum albuminconcentration.
 Treatment is administration of Ca,sometimeswith
vitamin D.
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 Hypercalcemia is total serum Caconcentration >10.4
mg/dL (> 2.60 mmol/L) or ionized serum Ca>5.2 mg/dL
(> 1.30 mmol/L).
 Principal causesinclude hyperparathyroidism, vitamin D
toxicity, andcancer.
 Clinical features include polyuria, constipation,muscle
weakness, confusion, and coma.
Diagnosis is by serum ionized Caand parathyroid
hormone concentrations.
Treatment to increase Caexcretion and reduce bone
resorption of Cainvolves saline, Nadiuresis, and drugs
such as pamidronate.
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