Disorders of Calcium, Disorders of Calcium, Phosphate and Phosphate and

Magnesium metabolismMagnesium metabolism

ContentsContents::

Calcium homeostasisCalcium homeostasis Biological function of calciumBiological function of calciumControl of calcium metabolismControl of calcium metabolismInvestigations of abnormal calcium metabolismInvestigations of abnormal calcium metabolismHypercalcemiaHypercalcemiaHypocalcemiaHypocalcemiaHypoparathyroidismHypoparathyroidismBiochemical bone diseasesBiochemical bone diseasesOsteoporosisOsteoporosis Phosphate metabolismPhosphate metabolismHypo- and hyperphosphatemiaHypo- and hyperphosphatemiaMagnesium metabolismMagnesium metabolism

IntroductionIntroduction

CalciumCalcium is is the most abundant mineral in the bodythe most abundant mineral in the body: : about 25 mol (1 kg) in a 70 kg man.about 25 mol (1 kg) in a 70 kg man.

~ ~ 99% of the body’s calcium is present in the bone99% of the body’s calcium is present in the bone, as , as hydroxyapatitehydroxyapatite ( (CaCa1010(PO(PO44))66(OH)(OH)22)), where it is , where it is combined combined with phosphatewith phosphate. .

CaCa2+2+ - means that - means that only calcium ionsonly calcium ions are being considered are being considered..

[calcium][calcium] : : total conc. of calciumtotal conc. of calcium in plasma or urinein plasma or urine . .

PlasmaPlasma [Ca[Ca2+2+]] :: the conc. of ionized calcium.the conc. of ionized calcium.

HypercalcemiaHypercalcemia & & hypocalcemiahypocalcemia are are relatively common relatively common biochemical abnormalitiesbiochemical abnormalities, as are , as are abnormalities in abnormalities in plasma [phosphate]. plasma [phosphate].

85% of the body’s phosphate85% of the body’s phosphate contentcontent is present is present in in the bonethe bone. .

Introduction ….. Introduction ….. ContdContd

Alterations in plasma [albuminAlterations in plasma [albumin]] ((the major calcium- the major calcium- binding protein in plasma)binding protein in plasma) abnormal plasma abnormal plasma [calcium][calcium] measurements. measurements.

Other casesOther cases result from result from or or unbound or ionized unbound or ionized calcium.calcium.

To estimate the physiologic levels of To estimate the physiologic levels of [Ca[Ca+2+2]] in states in states of hypoalbuminemia:of hypoalbuminemia:

[Ca[Ca+2+2]]CorrectedCorrected = = [Ca[Ca+2+2]]MeasuredMeasured + [ + [ 0.8 (4 – Albumin)0.8 (4 – Albumin)]]

Pathological levelsPathological levels of of [Ca[Ca+2+2] ] is is life threateninglife threatening . .

Introduction ….. Introduction ….. ContdContd

Calcium homeostasisCalcium homeostasis

Calcium balance:Calcium balance:

In adultsIn adults:: normally, normally, calcium intake = outputcalcium intake = output . .

In infancy and childhoodIn infancy and childhood:: there is normally a there is normally a positive positive

balancebalance, especially at times of active skeletal growth. , especially at times of active skeletal growth.

In older ageIn older age: : calcium output calcium output >> input input negative negative

balancebalance; ; marked in women after menopausemarked in women after menopause, ,

postmenopausal osteoporosispostmenopausal osteoporosis. .

In womenIn women, , the mother loses calcium to the fetus the mother loses calcium to the fetus

during pregnancyduring pregnancy and by and by lactationlactation..

External balanceExternal balance : : when the net absorption over 24 h when the net absorption over 24 h

= the corresponding 24 h urinary excretion; that = the corresponding 24 h urinary excretion; that

varies with the diet.varies with the diet.

Overview of Calcium BalanceOverview of Calcium Balance

Daily Calcium BalanceDaily Calcium Balance

DIET

(25 mmol/day)

INTESTINE

Net absorption = 5 mmol/day

10 mmol/day

absorbed

5 mmol/day

excreted KIDNEY

URINE LOSS

(5 mmol/day)

BONE

Rapid exchange Turnover (slow)

Biological function of calciumBiological function of calcium::

CalciumCalcium is a is a major mechanical constituent of the bonemajor mechanical constituent of the bone. .

Calcium in the boneCalcium in the bone acts as acts as a reservoira reservoir that helps to that helps to stabilize ECF [Castabilize ECF [Ca2+2+].].

BoneBone is a is a specialized mineralized connective tissuespecialized mineralized connective tissue containing:containing:– cellular elementscellular elements ( (bone-forming osteoblasts and bone - bone-forming osteoblasts and bone -

resorbing osteoclastsresorbing osteoclasts), ), – organic matrixorganic matrix ( (type I collagen, proteoglycan, etc.) type I collagen, proteoglycan, etc.)

– hydroxyapatitehydroxyapatite (the (the calcium-containing mineral)calcium-containing mineral)..

There is a There is a constant state of turnoverconstant state of turnover in the skeleton in the skeleton (about 5% per year of the adult skeleton is remodeled).(about 5% per year of the adult skeleton is remodeled).

Maintenance of extracellular [CaMaintenance of extracellular [Ca2+2+]] is necessary for is necessary for normal excitability of nerve and musclenormal excitability of nerve and muscle. .

[Ca[Ca2+2+]] threshold for thethreshold for the nerve action potentialnerve action potential and and vice versa.vice versa.

CaCa2+2+ is required in the is required in the activation of the clottingactivation of the clotting and and complement cascadescomplement cascades..

ECF [CaECF [Ca2+2+]] : : ~ 1 mmol/L (10~ 1 mmol/L (10—3—3 M). M).

Cytosolic [CaCytosolic [Ca2+2+]] is is much lowermuch lower : : ~ 100 nmol/L (10~ 100 nmol/L (10—7—7 M). M).

cytosolic [Ca2+]cytosolic [Ca2+] serves as a signal forserves as a signal for: :

• cell shape change cell shape change • cell motility cell motility • metabolic changes metabolic changes • secretory activity secretory activity • cell divisioncell division

Intercellular signalsIntercellular signals (including several hormones) (including several hormones) cytosolic [Ca2+] cytosolic [Ca2+] by: by:

• opening Caopening Ca2+2+ channels in channels in plasma membraneplasma membrane

• releasing intracellular releasing intracellular CaCa2+ 2+ stores stores

• combination of these combination of these effects.effects.

Control of calcium metabolism:Control of calcium metabolism:

Plasma [CaPlasma [Ca2+2+]] : : – the physiologically important the physiologically important

componentcomponent– regulated in humans by the regulated in humans by the

PTH &1: 25- (DHCC)PTH &1: 25- (DHCC)( both ( both plasma [Ca plasma [Ca2+2+] and ] and plasma [calcium] ).plasma [calcium] ).

plasma [Caplasma [Ca2+2+],], changes in PTH and 1 : 25-changes in PTH and 1 : 25-DHCC production. DHCC production.

‘‘calcium’ in the plasmacalcium’ in the plasma::Reference RangeReference Range

( 2.12 – 2.62 mmol/L)( 2.12 – 2.62 mmol/L)

( 3 forms)( 3 forms)

- -5050 - - 65%65% in ionized formin ionized form (the physiologically active form)(the physiologically active form)

- -3030 - - 45%45% bound to proteinsbound to proteins (predominantly albumin)(predominantly albumin)

- -55- - 10%10% complexed with anionscomplexed with anions ) ) citrate, sulfate, phosphatecitrate, sulfate, phosphate((

A. PTH

B. 1:25 DHCC

C. Calcitonin

Calcium metabolismCalcium metabolism is influenced also by:is influenced also by:

• Growth hormone Growth hormone • Glucocorticoids Glucocorticoids (cortisol)(cortisol) • Estrogens Estrogens • Testosterone Testosterone • Thyroid hormones Thyroid hormones

- - T4, thyroxin T4, thyroxin - T3, tri-iodothyronine.- T3, tri-iodothyronine.

A. Parathyroid hormone (PTH)A. Parathyroid hormone (PTH): :

PTHPTH is the is the principal acute regulator of plasma [Caprincipal acute regulator of plasma [Ca2+2+].].

Plasma PTH levelsPlasma PTH levels exhibit exhibit a diurnal rhythma diurnal rhythm::– highesthighest in the in the early hours of the morningearly hours of the morning – lowestlowest at about at about 9 AM9 AM. .

Active PTHActive PTH : :– secreted in response to a fall in plasma [Casecreted in response to a fall in plasma [Ca2+2+], ], – plasma [Caplasma [Ca2+2+].].

Low serum [CaLow serum [Ca+2+2] ] PTH secretion PTH secretion

High serum [CaHigh serum [Ca+2+2] ] PTH secretion PTH secretion

Role of PTHRole of PTH

Stimulates renal reabsorption of calciumStimulates renal reabsorption of calcium

Inhibits renal reabsorption of phosphateInhibits renal reabsorption of phosphate

Stimulates bone resorption by osteoclastsStimulates bone resorption by osteoclasts

Inhibits bone formation and mineralizationInhibits bone formation and mineralization

Stimulates synthesis of calcitriolStimulates synthesis of calcitriol

Net effect of PTH Net effect of PTH serum calciumserum calcium serum phosphateserum phosphate

Severe hyperparathyroidismSevere hyperparathyroidism subperiosteal resorption subperiosteal resorption of the terminal phalangesof the terminal phalanges, , bone cystsbone cysts & & pepper skull.pepper skull.

In the kidneyIn the kidney::

PTHPTH distal tubular reabsorption of calcium. distal tubular reabsorption of calcium. proximal tubular phosphate reabsorption proximal tubular phosphate reabsorption – promotes activity of the 1α-hydroxylation of promotes activity of the 1α-hydroxylation of

calcidiol.calcidiol.

Renal loss of HCORenal loss of HCO33-- a mild metabolic acidosis. a mild metabolic acidosis.

Formation of 1: 25-DHCC indirectlyFormation of 1: 25-DHCC indirectly Ca absorption Ca absorption from the small intestinefrom the small intestine..

Fall in plasma [Ca2+]

Parathyroid glands Stimulated by Plasma [Ca2+]

Ca absorption

On PTH release

-ve feedback effects of plasma [Ca2+]

On Renal 1-

hydroxylase

Plasma [PTH]

Plasma 1:25 DHCC

Plasma [Ca2+]

-ve feedback -ve feedback

BONE

SMALL INTESTINE

KIDNEY

Calcium Homeostasis

Most vitamin D3 (cholecalciferol)Most vitamin D3 (cholecalciferol) : :– synthesized bysynthesized by the the action of UV on the vitamin D action of UV on the vitamin D

precursorprecursor 7- dehydrocholesterol in the skin. 7- dehydrocholesterol in the skin.

– found infound in plenty amount in plenty amount in (fish oils),(fish oils), while vitamin while vitamin D (ergosterol) is added to margarine.D (ergosterol) is added to margarine.

– Endogenous synthesis of vitamin D3 is important.Endogenous synthesis of vitamin D3 is important.

1: 25-DihydroxychoIecalciferol (1: 25-DHCC, or calcitriol)1: 25-DihydroxychoIecalciferol (1: 25-DHCC, or calcitriol)

• inadequate exposure to sunlight inadequate exposure to sunlight • inadequate dietary intake.inadequate dietary intake.• combinedcombined

Vit. D deficiencyVit. D deficiencyis due to :is due to :

Role of 1:25 DHCC (Calcitriol)Role of 1:25 DHCC (Calcitriol)

Stimulates GI absorption of both calcium and Stimulates GI absorption of both calcium and phosphatephosphate through synthesis of a Ca through synthesis of a Ca2+2+-binding -binding protein in the intestinal epithelial cell necessary for protein in the intestinal epithelial cell necessary for CaCa2+2+ absorption . absorption .

Stimulates renal reabsorption of both calcium Stimulates renal reabsorption of both calcium and phosphateand phosphate..

Stimulates bone resorptionStimulates bone resorption..

Net effect of calcitriolNet effect of calcitriol↑↑ serum calciumserum calcium

↑↑ serum phosphateserum phosphate

Deficiency of 1: 25-DHCCDeficiency of 1: 25-DHCC defective bone mineralizationdefective bone mineralization. .

Effect of vitamin D on Effect of vitamin D on bone:bone:

l,25-diOH Dl,25-diOH D33 plasma plasma

calciumcalcium and and phosphatephosphate level level

by by stimulating the stimulating the

mobilization of calcium and mobilization of calcium and

phosphate from bonephosphate from bone in the in the

presence of presence of PTHPTH..

Formation of 1:25- DHCC (Calcitriol)Formation of 1:25- DHCC (Calcitriol)

Overview of Calcium-Phosphate RegulationOverview of Calcium-Phosphate Regulation

occurs in the liveroccurs in the liver 25-hydroxycholecalciferol 25-hydroxycholecalciferol (25-HCC, or calcidiol) production. (25-HCC, or calcidiol) production.

25-HCC, bind to a specific transport protein25-HCC, bind to a specific transport protein kidneykidney for further metabolism. for further metabolism.

Plasma [25-HCC]Plasma [25-HCC] shows shows seasonal variationseasonal variation ((highest highest in summer)in summer)..

25-Hydroxylation25-Hydroxylation : :

occurs in the kidneyoccurs in the kidney production of 1: 25-DHCCproduction of 1: 25-DHCC, , ((the most active naturally occurring derivative of vitamin D)the most active naturally occurring derivative of vitamin D)..

The kidney also contains 24-hydroxylaseThe kidney also contains 24-hydroxylase converts 25-HCC converts 25-HCC 24 : 25-DHCC. 24 : 25-DHCC.

Renal 1α-hydroxylation Renal 1α-hydroxylation by : by :– low plasma [phosphate]low plasma [phosphate]– high [PTH] high [PTH] – tendency to hypocalcemia.tendency to hypocalcemia.

1α - Hydroxylation of 25 - HCC1α - Hydroxylation of 25 - HCC::

CalcitoninCalcitonin: :

CalcitoninCalcitonin plasma [Ca plasma [Ca2+2+]] by: by: osteoclast activity osteoclast activity

renal reabsorption of calcium and phosphate.renal reabsorption of calcium and phosphate.

its actions are transient.its actions are transient.

chronic excess or deficiency is not associated chronic excess or deficiency is not associated with disordered calcium or bone metabolism.with disordered calcium or bone metabolism.

Used as a bone tumor marker Used as a bone tumor marker

Investigations of abnormal calcium Investigations of abnormal calcium metabolismmetabolism

Clinical biochemistry laboratories only measure plasma Clinical biochemistry laboratories only measure plasma [calcium] routinely because of the technical difficulties [calcium] routinely because of the technical difficulties associated with the measurement of [Caassociated with the measurement of [Ca2+2+].].

Diagnosis of most disordersDiagnosis of most disorders of calcium metabolismof calcium metabolism

depends ondepends on::

Measurement ofMeasurement of: : - -Plasma calcium & albuminPlasma calcium & albumin

- -Inorganic phosphateInorganic phosphate - ALPALP

-SometimesSometimes:: - - magnesiummagnesium

- - PTHPTH - - vitamin D metabolitesvitamin D metabolites

Plasma calcium reference range ( 2.12—2.62 mmol/L)Plasma calcium reference range ( 2.12—2.62 mmol/L)

Effects of plasma [albumin]Effects of plasma [albumin]: :

plasma [albumin]plasma [albumin] bound calcium & bound calcium & total total [calcium] (and vice versa). [calcium] (and vice versa).

Under these circumstances, the unbound plasma [CaUnder these circumstances, the unbound plasma [Ca2+2+], ], will be maintained at normal levels by PTH.will be maintained at normal levels by PTH.

Abnormal calcium binding, due to Abnormal calcium binding, due to plasma [albumin] plasma [albumin] modest but potentially misleading modest but potentially misleading in plasma [calcium] in plasma [calcium]

Plasma [albumin]Plasma [albumin] should always be measured at the should always be measured at the same time as plasma [calcium]same time as plasma [calcium] to avoid misdiagnosis of to avoid misdiagnosis of hypo- or hypercalcemia.hypo- or hypercalcemia.

Plasma ConcentrationsPlasma ConcentrationsLevelsLevels[Total calcium][Total calcium]NormalNormalLowLowHighHigh

[Free Ca[Free Ca2+2+]]NormalNormalNormalNormalNormalNormal

[Albumin][Albumin]NormalNormalLowLowHighHigh

[Albumin-bound Ca[Albumin-bound Ca2+2+]]NormalNormalLowLowHighHigh

To

tal Calciu

mT

otal C

alcium

Free Calcium IonsFree Calcium Ions

Calcium ions bound to Calcium ions bound to AlbuminAlbumin

CalciumCalcium complexed to complexed to citratecitrate

Effects of plasma [albumin]Effects of plasma [albumin] on Calcium distribution on Calcium distribution

Normal

Low

High

The plasma [calcium]The plasma [calcium] (in mmol/L) can be (in mmol/L) can be approximately approximately ‘corrected’‘corrected’ to take account of an to take account of an abnormal albumin (in g/L) using a formula such abnormal albumin (in g/L) using a formula such as:as:

‘‘Corrected’Corrected’ [calcium] = [calcium] =

measuredmeasured [calcium] [calcium] ++ 0.02 0.02 xx (40- [albumin]) (40- [albumin])

Effects of plasma HEffects of plasma H ++: :

In acidosisIn acidosis, protonation of albumin , protonation of albumin its ability to bind its ability to bind calcium calcium unbound [Caunbound [Ca2+2+]] and vice versa, without any and vice versa, without any change in total [calcium]. change in total [calcium].

HyperventilationHyperventilation respiratory alkalosisrespiratory alkalosis plasma plasma [Ca[Ca2+2+]] TetanyTetany. .

In chronic states of acidosis or alkalosisIn chronic states of acidosis or alkalosis, , PTHPTH readjust the plasma [Careadjust the plasma [Ca2+2+] back to normal] back to normal..

Diurnal variationDiurnal variation, especially following meals; , especially following meals;

VariableVariable in different age groups. in different age groups.

~ 85% of plasma phosphate~ 85% of plasma phosphate is is free free and and

15%15% protein bound.protein bound.

Plasma phosphate (reference range O.8 — 1.4 mmol/L)Plasma phosphate (reference range O.8 — 1.4 mmol/L)( fasting level )( fasting level )

Alkaline phosphataseAlkaline phosphatase::

Physiological variationsPhysiological variations in enzyme’s activity in: in enzyme’s activity in: – Childhood Childhood – Adolescence Adolescence – Pregnancy.Pregnancy.

PathologicalPathological : :osteoblastic activity osteoblastic activity ALP ALP activity e.g.:activity e.g.:– Hyperparathyroidism Hyperparathyroidism – Paget’s disease Paget’s disease

– Rickets and osteomalacia Rickets and osteomalacia

Carcinoma osteoblastic metastasesCarcinoma osteoblastic metastases..

HYPERCALCEMIAHYPERCALCEMIA

plasma [Ca2+]plasma [Ca2+]• Renal damageRenal damage• Cardiac arrhythmias Cardiac arrhythmias • General ill-healthGeneral ill-health

• 1ry hyperparathyroidism (1ry hyperparathyroidism (80%)• MalignanciesMalignanciesCommonest causesCommonest causes

Clinical consequences of high [CaClinical consequences of high [Ca2+2+]]

Neurological Symptoms:Neurological Symptoms:– Inability to concentrateInability to concentrate– Depression Depression – ConfusionConfusion

Generalized Muscle weakness.Generalized Muscle weakness.Anorexia , nausea, vomiting , constipation.Anorexia , nausea, vomiting , constipation.Polyuria with polydipsia.Polyuria with polydipsia.Nephrocalcinosis, NephrolithasisNephrocalcinosis, NephrolithasisECG changes (shortened Q-T interval ) with ECG changes (shortened Q-T interval ) with bradycardia, and first-degree block. bradycardia, and first-degree block.Pancreatitis.Pancreatitis.Peptic ulcer.Peptic ulcer.

Etiologies of HypercalcemiaEtiologies of Hypercalcemia

Increased GI AbsorptionIncreased GI Absorption- Milk-alkali syndrome- Milk-alkali syndrome- Elevated calcitriol:- Elevated calcitriol: - Vitamin D excess- Vitamin D excess

- Excessive dietary intake- Excessive dietary intake - Granuomatous diseases:- Granuomatous diseases:

- Elevated PTH- Elevated PTH- Hypophosphatemia- Hypophosphatemia

Increased Loss From BoneIncreased Loss From Bone- Increased net bone resorption- Increased net bone resorption- Elevated PTH - Elevated PTH

(Hyperparathyroidism)(Hyperparathyroidism)- Malignancy:- Malignancy: - Osteolytic metastases- Osteolytic metastases - PTHrP secreting tumor- PTHrP secreting tumor

Increased bone turnoverIncreased bone turnover - Paget’s disease of bone- Paget’s disease of bone - Hyperthyroidism- Hyperthyroidism

Decreased Bone Mineralization

- Elevated PTH

- Aluminum toxicity

Decreased Urinary Excretion

- Thiazide diuretics

- Elevated calcitriol

- Elevated PTH

Causes of hypercalcemiaCauses of hypercalcemia

CategoryCategoryExamplesExamples

Common:Common:Parathyroid diseaseParathyroid disease

Malignant diseaseMalignant disease

- Hyperparathyroidism, primary and tertiary; multiple - Hyperparathyroidism, primary and tertiary; multiple endocrine neoplasia syndromes, MEN I and MEN haendocrine neoplasia syndromes, MEN I and MEN ha

- - Lytic lesions in bone: myeloma, breast carcinomaLytic lesions in bone: myeloma, breast carcinoma

- PTHrP: carcinoma of lung, esophagus, head and - PTHrP: carcinoma of lung, esophagus, head and neck, renal cell, ovary and bladderneck, renal cell, ovary and bladder

- Ectopic production of 1: 25-DHCC by lymphomas- Ectopic production of 1: 25-DHCC by lymphomas

UncommonUncommon

Endogenous production of 1: 25-DHCCEndogenous production of 1: 25-DHCC

Excessive absorption of calciumExcessive absorption of calcium

Bone diseaseBone disease

Drug-inducedDrug-induced

- Sarcoidosis and other granulomatous diseases- Sarcoidosis and other granulomatous diseases

- - Vitamin D overdose (including self-medication) Vitamin D overdose (including self-medication) milk-alkali syndromemilk-alkali syndrome

- - ImmobilizationImmobilization

- - Thiazide diuretics, lithiumThiazide diuretics, lithium

Miscellaneous (mostly rare)Miscellaneous (mostly rare)

ArtefactArtefact

- Familial hypocalciuric hypercalcaemia- Familial hypocalciuric hypercalcaemia

- Hypercalcaemia in childhood - Hypercalcaemia in childhood

- Thyrotoxicosis- Thyrotoxicosis

- Addison’s disease- Addison’s disease

- Poor venepuncture technique (Venous Stasis)- Poor venepuncture technique (Venous Stasis)

Primary hyperparathyroidismPrimary hyperparathyroidism::

• Single, parathyroid Single, parathyroid adenomaadenoma. . • Diffuse Diffuse hyperplasiahyperplasia (involving all four glands) (involving all four glands) • Rarely, parathyroid Rarely, parathyroid carcinomacarcinoma

PTHPTH

• [Ca[Ca2+2+], with the potential for clinical problems. ], with the potential for clinical problems. • Plasma [phosphate] due to its phosphaturic effect.Plasma [phosphate] due to its phosphaturic effect.

PTH PTH urinary HCO urinary HCO3-3- losses losses mild metabolic acidosis mild metabolic acidosis

plasma [PTH] plasma [PTH] bony problems if chronic. bony problems if chronic.

Markers of Markers of osteoblast & osteoclast activity may be osteoblast & osteoclast activity may be ..

‘‘First-line’ biochemical tests for investigating First-line’ biochemical tests for investigating suspected hyperparathyroidismsuspected hyperparathyroidism..

Plasma or serumPlasma or serum CommentsComments

- Calcium- Calcium

- Albumin- Albumin

-- Phosphate (fasting)Phosphate (fasting)

- ALP- ALP

- Total CO2- Total CO2

--Creatinine / ureaCreatinine / urea

- If - If [calcium], supports the diagnosis [calcium], supports the diagnosis

- Should be performed as a check on - Should be performed as a check on plasma [calcium]plasma [calcium]

- If - If [phosphate], supports the diagnosis [phosphate], supports the diagnosis

- If enzymic activity - If enzymic activity , supports the diagnosis, supports the diagnosis

- If - If , supports the diagnosis, supports the diagnosis

- - Simple tests of renal function, needed in all Simple tests of renal function, needed in all patients with suspected abnormalities of patients with suspected abnormalities of

calcium metabolism PTHcalcium metabolism PTH

PTH assayPTH assay

Measurement of serum PTHMeasurement of serum PTH is the single most important is the single most important test in the differential diagnosis of hypercalcaemia. test in the differential diagnosis of hypercalcaemia.

Immunometric (‘sandwich’) assaysImmunometric (‘sandwich’) assays that measure that measure serum [intact PTH] (reference range 10—55 ng/L) are serum [intact PTH] (reference range 10—55 ng/L) are now in widespread use. now in widespread use.

90% of patients with primary hyperparathyroidism90% of patients with primary hyperparathyroidism have an have an level level (high diagnostic sensitivity) (high diagnostic sensitivity)..

10% of patients10% of patients with primary hyperparathyroidismwith primary hyperparathyroidism may have serum [intact PTH] in the upper part of the may have serum [intact PTH] in the upper part of the reference range.reference range.

A sestamibi parathyroid imagingA sestamibi parathyroid imaging scan may also be scan may also be useful.useful.

Biochemical investigation of persistent hypercalcemia

Persistent

Hypercalcemia (adjusted

for albumin)

Exclude

Drug Therapy Thiazides,

Lithium Vitamin D

Intact PTHHighPHPT- up to 90 % of patients have raised levels

Suppressed or Lower half of

reference range

• Exclude Malignancy

• Other non-parathyroid causes of hypercalcemia should be considered.

• Measurement of PTHrP may be helpful

Upper half of Reference range or Borderline of high

• PHPT- up to 10 % of patients.

• Exclude FBHH by Calcium excretion and family study.

• PHPT : primary Hyperparathyroidism.

• FBHH : familial Benign Hypocalciuric Hypercalcemia.

• Patients with malignancy-associated Hypercalcemia may have coexisting PHPT.

• Samples for intact PTH should be taken before any active treatment to reduce hypercalcemia.

Management of primary hyperparathyroidismManagement of primary hyperparathyroidism

Careful clinical Careful clinical reassessment.reassessment.

has technical difficulty.has technical difficulty.

not indicated in patients not indicated in patients with asymptomatic with asymptomatic hyperparathyroidism if hyperparathyroidism if their plasma [calcium] is their plasma [calcium] is less than 3.0 mmol/L. less than 3.0 mmol/L.

Parathyroid surgeryParathyroid surgery Follow up Follow up

Regular measurements Regular measurements of plasma of plasma [calcium] .[calcium] .

Indications for parathyroidectomyIndications for parathyroidectomy: : includeinclude

(a) (a) Presence of symptomsPresence of symptoms; a urine calcium excretion over 9 ; a urine calcium excretion over 9 mmol/ 24 h. mmol/ 24 h.

(b) (b) Cortical radial bone densityCortical radial bone density over 2 SD below normal. over 2 SD below normal.(c) (c) Reduced creatinine clearanceReduced creatinine clearance (if no other cause identified). (if no other cause identified). (d) (d) Age under 50 yearsAge under 50 years..

It is advisable to doIt is advisable to do parathyroidectomy parathyroidectomy early rather than late. early rather than late.

• Plasma [calcium] falls rapidlyPlasma [calcium] falls rapidly, should be measured several times on , should be measured several times on the first post-operative day and at least daily for the next few days. the first post-operative day and at least daily for the next few days.

• If the plasma [calcium] falls below normalIf the plasma [calcium] falls below normal::

• calcium gluconatecalcium gluconate should be given. should be given. • 1:25-DHCC or 11:25-DHCC or 1-hydroxy cholecalciferol should be started.-hydroxy cholecalciferol should be started.

After parathyroidectomy:

Multiple endocrine neoplasia (MEN) Multiple endocrine neoplasia (MEN) syndromessyndromes . .

1ry hyperparathyroidism1ry hyperparathyroidism may be one of the may be one of the abnormalities in the so-called MEN syndrome. abnormalities in the so-called MEN syndrome.

3 types3 types of MEN syndrome have been of MEN syndrome have been described, described, all of them familial. all of them familial.

Hypercalcemia of malignancyHypercalcemia of malignancy

Several factorsSeveral factors are responsible for the hypercalcemia of are responsible for the hypercalcemia of malignancy.malignancy.

Depending onDepending on::– the type of tumor the type of tumor – whether or not there are bone metastases. whether or not there are bone metastases.

1.1. Solid tumorsSolid tumors metastasized metastasized to bone to bone hypercalcaemiahypercalcaemia (by paracrine activation of (by paracrine activation of osteoclasts). osteoclasts).

The tumor cells The tumor cells bone bone resorptionresorption directly. directly.

2.2. Some solid tumorsSome solid tumors (e.g. (e.g. carcinoma of the lung, head carcinoma of the lung, head and neck), and neck),

in the absence of bony in the absence of bony metastasesmetastases HypercalcemiaHypercalcemia

3.3. In multiple myeloma:In multiple myeloma:

Local cytokines Local cytokines local bone resorption local bone resorption hypercalcemia.hypercalcemia.

Lymphomas Lymphomas hypercalcemia. hypercalcemia.

Serum [intact PTH] is usually suppressed in Serum [intact PTH] is usually suppressed in patients with malignancy-associated patients with malignancy-associated

hypercalcemia.hypercalcemia.

An important factor in humoral hypercalcemia of An important factor in humoral hypercalcemia of malignancy.malignancy.

A peptideA peptide with marked sequence homology with PTH that with marked sequence homology with PTH that acts through the PTH receptoracts through the PTH receptor..

PTHrPPTHrP may also be secreted by some tumors that may also be secreted by some tumors that metastasize to bone.metastasize to bone.

HumoralHumoral and and local osteolytic mechanismslocal osteolytic mechanisms combine combine hypercalcemia.hypercalcemia.

True ectopic production of PTHTrue ectopic production of PTH appears to be appears to be rare.rare.

Assays for PTHrPAssays for PTHrP are are available in specialist available in specialist laboratorieslaboratories and may be helpful in the investigation of and may be helpful in the investigation of patients with unexplained hypercalcemia.patients with unexplained hypercalcemia.

PTH-related Protein (PTHrP)PTH-related Protein (PTHrP)

Oth

er c

ause

s o

f h

yper

calc

emia

Oth

er c

ause

s o

f h

yper

calc

emia

Other bone – related causes (Paget’s disease)

Vitamin D excessVitamin D excess

Drugs (Thiazide diuretics, Lithium)Drugs (Thiazide diuretics, Lithium)

SarcoidosisSarcoidosis

Tertiary hyperparathyroidism Tertiary hyperparathyroidism

Familial benign hypocalciuric hypercalcemia (FBHH)Familial benign hypocalciuric hypercalcemia (FBHH)

Endocrine disorders Endocrine disorders

Milk-alkali syndrome

Excessive vitamin D intakeExcessive vitamin D intake ( or overdosage with ( or overdosage with 25-HCC, 1α-HCC or 1: 25-DHCC occurs)25-HCC, 1α-HCC or 1: 25-DHCC occurs) plasma plasma [1 : 25-DHCC] [1 : 25-DHCC] hypercalcemia. hypercalcemia.

Vitamin D excessVitamin D excess::

Thiazide diureticsThiazide diuretics mild mild hypercalcemiahypercalcemia interfere interfere with renal calcium excretion.with renal calcium excretion.

Long- term lithium therapyLong- term lithium therapy stimulating PTH stimulating PTH secretion secretion hypercalcemiahypercalcemia..

Drugs:Drugs:

~ 10-20% of sarcoidosis patients have ~ 10-20% of sarcoidosis patients have hypercalcemiahypercalcemia. . they have they have hypercalciuria.hypercalciuria. Unregulated conversion of 25-HCC Unregulated conversion of 25-HCC 1 : 25-DHCC by 1 : 25-DHCC by sarcoid tissue macrophages is responsible. sarcoid tissue macrophages is responsible.

SarcoidosisSarcoidosis : :

Tertiary hyperparathyroidismTertiary hyperparathyroidism::

Development of parathyroid hyperplasia as a Development of parathyroid hyperplasia as a complication of previous 2ry hyperparathyroidism. complication of previous 2ry hyperparathyroidism. Plasma [calcium]. Plasma [calcium]. serum [PTH]. serum [PTH]. fasting plasma [phosphate] if it develops in a patient fasting plasma [phosphate] if it develops in a patient with renal failure.with renal failure.

Familial benign hypocalciuric hypercalcemia Familial benign hypocalciuric hypercalcemia (FBHH(FBHH))

Autosomal dominant disorderAutosomal dominant disorder

Usually asymptomaticUsually asymptomatic

Population prevalence of up to 1: 16.000Population prevalence of up to 1: 16.000

A mutation in the Calcium-sensing receptor gene in the A mutation in the Calcium-sensing receptor gene in the parathyroid gland, kidney and other organsparathyroid gland, kidney and other organs

plasma [Caplasma [Ca2+2+ ] that is sensed as ‘normal’ ] that is sensed as ‘normal’

Normal or Normal or plasma [PTH] plasma [PTH]

FBHH is distinguished from primary hyperparathyroidism FBHH is distinguished from primary hyperparathyroidism since parathyroidectomy since parathyroidectomy (does not (does not plasma [Ca2+], and plasma [Ca2+], and no active treatment is indicated)no active treatment is indicated)

In FBHHIn FBHH::– urinary calcium is usually low urinary calcium is usually low – plasma [Mg] tends to be high normal.plasma [Mg] tends to be high normal.

Combination of family studies and measurement of Combination of family studies and measurement of calcium excretion together with plasma [Mg] is calcium excretion together with plasma [Mg] is helpful in identifying the condition. helpful in identifying the condition.

Calcium excretion (CE )Calcium excretion (CE ) : :– measured on a second void spot urine and blood measured on a second void spot urine and blood

sample obtained after an overnight fastsample obtained after an overnight fast– calculated by calculated by multiplyingmultiplying : the urine calcium : the urine calcium

creatinine ratio (both in mmol/L) creatinine ratio (both in mmol/L) byby the serum the serum creatinine (in creatinine (in mol/L).mol/L).

CaCaEE < 14 < 14 mol/L GF suggests FBHH.mol/L GF suggests FBHH.

Hypoadrenalism, phaeochromocytoma and Hypoadrenalism, phaeochromocytoma and thyrotoxicosis thyrotoxicosis Hypercalcemia. Hypercalcemia.

Endocrine disorders:Endocrine disorders:

Milk—alkali syndromeMilk—alkali syndrome::

Excessive milk consumptionExcessive milk consumption in patients with peptic in patients with peptic ulceration ulceration calcium intake . calcium intake .If this is accompanied by If this is accompanied by excessive intake of alkaliexcessive intake of alkali (e.g. (e.g. NaHCONaHCO33), as an antacid ), as an antacid hypercalcemia. hypercalcemia. The alkali The alkali urinary calcium excretion urinary calcium excretion hypercalcemia.hypercalcemia.

Other bone-related causes:Other bone-related causes:

Paget’s diseasePaget’s disease in association with immobilization. in association with immobilization.

HYPOCALCEMIAHYPOCALCEMIA

- Tetany- Tetany, ,

- Neuropsychiatric symptoms- Neuropsychiatric symptoms - Cataract- Cataract

Misleading hypocalcemiaMisleading hypocalcemiadue todue to::

• Contamination of the Contamination of the sample with EDTAsample with EDTA (from (from a full blood count tube)a full blood count tube)

• plasma [albumin]plasma [albumin]

It should be excludedIt should be excluded

Pathological hypocalcemiaPathological hypocalcemiadue to due to in plasma [Cain plasma [Ca2+2+]]

A symptom suggests the presence of A symptom suggests the presence of low plasma [Calow plasma [Ca2+2+].].

May be May be caused bycaused by a a rapid fall in plasma [Ca2+]rapid fall in plasma [Ca2+] e.g.: e.g.:

Acute respiratory alkalosis due to hyperventilation. Acute respiratory alkalosis due to hyperventilation.

IV infusion of NaHCOIV infusion of NaHCO-3-3. .

OccasionallyOccasionally it is due to a it is due to a low plasma [Mglow plasma [Mg2+2+]] in the in the

absence of low plasma [Caabsence of low plasma [Ca2+2+],],

RarelyRarely it is due to sudden it is due to sudden in plasma [phosphate]. in plasma [phosphate].

TetanyTetany

Causes of hypocalcemiaCauses of hypocalcemia

CategoryCategory ExamplesExamples - Artifact- Artifact

- Hypoproteinemia- Hypoproteinemia

- Renal disease- Renal disease

- Inadequate intake of - Inadequate intake of calciumcalcium

- Hypoparathyroidism- Hypoparathyroidism

- - PseudohypoparathyroidismPseudohypoparathyroidism

- Neonatal hypocalcemia- Neonatal hypocalcemia

- Acute pancreatitis- Acute pancreatitis

- Critical illness- Critical illness

- - EDTA contaminator of sampleEDTA contaminator of sample- Low plasma [albumin] Low plasma [albumin] - Hydroxylation of 25-HCC impairedHydroxylation of 25-HCC impaired

- Deficiency of calcium or vitamin D, or of - Deficiency of calcium or vitamin D, or of both; intestinal malabsorptionboth; intestinal malabsorption

- Autoimmune, post-surgical, Mg - Autoimmune, post-surgical, Mg deficiency, infiltrative disease deficiency, infiltrative disease

- Target organ resistance to PTH- Target organ resistance to PTH

- - Calcium soaps in the abdominal cavity?Calcium soaps in the abdominal cavity?

- Mixed pathology — not clearly defined- Mixed pathology — not clearly defined

Etiologies of HypocalcemiaEtiologies of Hypocalcemia GI AbsorptionGI Absorption

- Poor dietary intake of calcium- Poor dietary intake of calcium - Impaired absorption of calcium- Impaired absorption of calcium

Vitamin D deficiencyVitamin D deficiency - Poor dietary intake of vitamin D- Poor dietary intake of vitamin D

- Malabsorption syndromes- Malabsorption syndromesDecreased conversion of vit. D to Decreased conversion of vit. D to

calcitriolcalcitriol - Liver failure- Liver failure - Renal failure- Renal failure - Low PTH- Low PTH - Hyperphosphatemia- Hyperphosphatemia

Bone Resorption/ Bone Resorption/ Mineralization Mineralization - Low PTH (hypoparathyroidism)- Low PTH (hypoparathyroidism) - PTH resistance ( pseudohypoparathyroidism)- PTH resistance ( pseudohypoparathyroidism) - Vitamin D deficiency / low calcitriol- Vitamin D deficiency / low calcitriol - Hungry bones syndrome- Hungry bones syndrome - Osteoblastic metastases- Osteoblastic metastases

Increased Urinary Excretion

Low PTH

- thyroidectomy

- I131 treatment

- Autoimmune hypoparathyroidism

- PTH resistance

- Vitamin D deficiency / low calcitriol

Clinical consequences of hypocalcemiaClinical consequences of hypocalcemia

Enhanced neuromuscular irritabilityEnhanced neuromuscular irritability (positive (positive

Chvostek’s sign and Trousseau’s sign);Chvostek’s sign and Trousseau’s sign); tetanytetany

Numbness, tinglingNumbness, tingling (fingers, toes, circumoral)(fingers, toes, circumoral)

Muscle crampsMuscle cramps (legs, feet, lower back)(legs, feet, lower back)

SeizuresSeizures

Irritability, personality changesIrritability, personality changes

ECG changesECG changes (prolonged Q —T interval)(prolonged Q —T interval)

Basal ganglia calcificationBasal ganglia calcification; ; subcapsular cataractssubcapsular cataracts

(especially with low PTH)(especially with low PTH)

Effect of Vitamin D deficiencyEffect of Vitamin D deficiency::

Inadequate plasma levels of 1:25-DHCCInadequate plasma levels of 1:25-DHCC defective defective calcium absorption calcium absorption hypocalcemiahypocalcemia (the commonest (the commonest pathological cause).pathological cause).

Deficiency of 1:25-DHCCDeficiency of 1:25-DHCC may result from: may result from:– lack of vitamin D or lack of vitamin D or – failure at any stage in its conversion to 1: 25-DHCC failure at any stage in its conversion to 1: 25-DHCC

In malnutritionIn malnutrition, , vitamin D deficiencyvitamin D deficiency together with together with inadequate dietary calcium inadequate dietary calcium hypocalcemiahypocalcemia

Defective absorption of calciumDefective absorption of calcium plasma [Ca2+] + plasma [Ca2+] + PTH secretion in response to the low ECF [CaPTH secretion in response to the low ECF [Ca2+2+] ] (i.e. (i.e. 2ry hyperparathyroidism).2ry hyperparathyroidism).

Plasma [phosphate]Plasma [phosphate] due to: due to:– impaired absorptionimpaired absorption– secondary hyperparathyroidismsecondary hyperparathyroidism

Plasma ALP activityPlasma ALP activity reflecting reflecting osteoblastic activity. osteoblastic activity.

Urinary calcium excretionUrinary calcium excretion . .

Confirmation of the diagnosis of vitamin D deficiencyConfirmation of the diagnosis of vitamin D deficiency depends ondepends on : :– measurement of serum [25-HCC] ormeasurement of serum [25-HCC] or– Measurement of serum [1:25-DHCC].Measurement of serum [1:25-DHCC].

11 . .Nutritional deficiency of vitamin DNutritional deficiency of vitamin D::

Poor dietPoor diet and/or and/or inadequate exposure to suninadequate exposure to sun light light, , vitamin D deficiencyvitamin D deficiency hypocalcemiahypocalcemia & & osteomalaciaosteomalacia ..

Eliminated in developed countriesEliminated in developed countries with vitamin D with vitamin D supplementation of food.supplementation of food.

The The elderly are at riskelderly are at risk (as they may be immobile indoors (as they may be immobile indoors with an inadequate diet).with an inadequate diet).

22 . .Malabsorption of vitamin DMalabsorption of vitamin D::

Due to: Due to: celiac diseaseceliac disease, or, orfat malabsorptionfat malabsorption due to: due to:– pancreatic diseasepancreatic disease, , – biliary obstructionbiliary obstruction, , – complication of gastric or intestinal surgery complication of gastric or intestinal surgery

(e.g. intestinal bypass or resection). (e.g. intestinal bypass or resection).

Biliary obstructionBiliary obstruction rather than 25-HCC deficiency rather than 25-HCC deficiency in parenchymal liver disease in parenchymal liver disease malabsorption malabsorption vitamin D deficiencyvitamin D deficiency. .

33 . .Renal diseaseRenal disease::

Destruction of the renal parenchymaDestruction of the renal parenchyma loss of activity loss of activity of 1α-hydroxylase of 1α-hydroxylase 1:25-DHCC formation 1:25-DHCC formation calcium calcium malabsorption . malabsorption .

plasma [phosphate] in renal failureplasma [phosphate] in renal failure interfere with the interfere with the 1α-hydroxylation step.1α-hydroxylation step.

In vitamin D-resistant rickets, type IIn vitamin D-resistant rickets, type I (a rare inherited (a rare inherited disorder)disorder) hypocalcemia hypocalcemia 1α-hydroxylase deficiency. 1α-hydroxylase deficiency.

In vitamin D-resistant rickets, type IIIn vitamin D-resistant rickets, type II, there is end-organ , there is end-organ unresponsiveness to 1:25-DHCC.unresponsiveness to 1:25-DHCC.

HypoparathyroidismHypoparathyroidism

The combination of The combination of plasma [calcium] and plasma [calcium] and [phosphate] [phosphate] in in absence renal disease absence renal disease diagnosis of diagnosis of hypoparathyroidismhypoparathyroidism..

Plasma ALP activity is usually normalPlasma ALP activity is usually normal..

[intact PTH] confirms the diagnosis[intact PTH] confirms the diagnosis to < 10 ng/L to < 10 ng/L (Sometimes undetectable even by the most sensitive assays).(Sometimes undetectable even by the most sensitive assays).

A. Primary hypoparathyroidisrnA. Primary hypoparathyroidisrn is rare is rare..

Failure to secrete PTHFailure to secrete PTH may be due to : may be due to : A complication of surgeryA complication of surgery FamilialFamilial Destruction of parathyroid glands by:Destruction of parathyroid glands by:

an autoimmune processan autoimmune process infiltration by carcinoma of thyroid or metastasisinfiltration by carcinoma of thyroid or metastasis

B. Secondary hypoparathyroidismB. Secondary hypoparathyroidism

AA rare rare but interesting condition. but interesting condition.

The end-organ receptors in the bone and kidneys The end-organ receptors in the bone and kidneys fail to respond normally to PTH. fail to respond normally to PTH.

There is There is serum [PTH]. serum [PTH].

In patients with magnesium deficiency.In patients with magnesium deficiency.

Normal magnesiumNormal magnesium levels are levels are necessary fornecessary for:: PTH release PTH release end-organ response to PTH.end-organ response to PTH.

C. PseudohypoparathyroidismC. Pseudohypoparathyroidism : :

Biochemical bone diseasesBiochemical bone diseases

Generalized defects in bone mineralisationGeneralized defects in bone mineralisation, , frequently associated with abnormal calcium or frequently associated with abnormal calcium or phosphate metabolism, phosphate metabolism, "biochemical or metabolic "biochemical or metabolic bone diseases".bone diseases".

OsteoporosisOsteoporosis

Rickets Rickets

OsteomalaciaOsteomalacia

Paget’s disease. Paget’s disease.

The most The most commoncommon

Metabolic bone diseaseMetabolic bone disease Chemical investigations on blood specimens Chemical investigations on blood specimens..

DiagnosisDiagnosis CalciumCalcium Phosphate Phosphate

(fasting)(fasting) PTHPTH ALPALP

CaCa22++

HyperparathyroidismHyperparathyroidism

- primary- primary

- Secondary- Secondary

- Tertiary- Tertiary

Rickets& osteomalaciaRickets& osteomalacia

- Deficient intake- Deficient intake

- Renal failure- Renal failure

- Fanconi’s syndrome- Fanconi’s syndrome

OsteoporosisOsteoporosis

Paget’s diseasePaget’s disease

(or N)(or N)

or Nor N

or Nor N

or Nor N

or Nor N

or Nor N

NN

N (orN (or))

(or N)(or N)

or Nor N

or Nor N

or Nor N

or Nor N

or Nor N

NN

NN

or Nor N

(or N)(or N)

NN

NN

NN

N orN or

or Nor N

or Nor N

NN

(or N)(or N)

NN

N (or N (or ))

NN

NN

NN

NN

Markers of bone turnoverMarkers of bone turnover

– cannotcannot reveal bone content in the skeleton. reveal bone content in the skeleton. – cannotcannot substitute for bone mineral density substitute for bone mineral density

measurement. measurement.

– used inused in the assessment of fracture risk. the assessment of fracture risk. – used inused in the monitoring of the response to the monitoring of the response to

therapy.therapy.

Biochemical markersBiochemical markers of bone turnoverof bone turnover

Bone resorptionBone resorption Bone formationBone formation

enzymesenzymes and and peptidespeptides released released by the osteoblast at the time of by the osteoblast at the time of

bone formationbone formation

a measure of the a measure of the breakdown products ofbreakdown products of

type 1 collagentype 1 collagen

Bone markers Bone markers

The most sensitive biochemical The most sensitive biochemical markers of bone tumormarkers of bone tumor

FormationFormation ResorptionResorption

SerumSerum- - Bone Alkaline phosphataseBone Alkaline phosphatase

- Osteoclasin- Osteoclasin

- Procollagen type - Procollagen type 1 N-terminal 1 N-terminal PropeptidePropeptide

UrineUrine

- - C - telopeptide cross C - telopeptide cross links (CTX)links (CTX)

- N - telopeptide cross - N - telopeptide cross links (NTX)links (NTX)

- Deoxypyridinoline- Deoxypyridinoline

Rickets and osteomalaciaRickets and osteomalacia

– Bone pain Bone pain – Local tendernessLocal tenderness – Proximal myopathy Proximal myopathy – Skeletal deformity may Skeletal deformity may

be present be present (in rickets).(in rickets). – Defective mineralisation Defective mineralisation

of osteoid tissueof osteoid tissue

Vitamin D deficiencyVitamin D deficiency or disturbed vitamin D or disturbed vitamin D metabolismmetabolism

OsteomalaciaOsteomalacia in adults, or in adults, or RicketsRickets in children in children

In Fanconi’s syndromeIn Fanconi’s syndrome, , tubular phosphate loss tubular phosphate loss plasma [phosphate] plasma [phosphate] rickets or osteomalacia. rickets or osteomalacia.

HypophosphatasiaHypophosphatasia : :

A hereditary disease .A hereditary disease .

Vitamin D-resistant rickets is the most prominent Vitamin D-resistant rickets is the most prominent finding. finding.

Tissue and plasma ALP activities are usually low.Tissue and plasma ALP activities are usually low.

Excessive amounts of phosphoryl ethanolamine are Excessive amounts of phosphoryl ethanolamine are present in the urine.present in the urine.

OsteoporosisOsteoporosis

A very common disorder.A very common disorder.

Affects about 25% of women.Affects about 25% of women.

Characterized by low bone mass and susceptibility Characterized by low bone mass and susceptibility to vertebral, forearm and hip fractures in later life.to vertebral, forearm and hip fractures in later life.

Results of routine chemical investigations are Results of routine chemical investigations are usually all normal.usually all normal.

• primary hyperparathyroidism.primary hyperparathyroidism. • thyrotoxicosis. thyrotoxicosis. • corticosteroid excess. corticosteroid excess. • multiple myeloma. multiple myeloma. • hypogonadism.hypogonadism.

The diagnosisThe diagnosis should excludeshould exclude::

Risk factors for osteoporosisRisk factors for osteoporosis

UnmodifiableUnmodifiable AgeAge (1.4 -1.8 - fold increase per decade) (1.4 -1.8 - fold increase per decade)

GeneticGenetic (Caucasians & Orientals > Blacks & Polynesians) (Caucasians & Orientals > Blacks & Polynesians)

SexSex (female > male) (female > male)

Modifiable (Environmental)Modifiable (Environmental) Nutritional calcium deficiencyNutritional calcium deficiency

Physical inactivityPhysical inactivity

SmokingSmoking

Alcohol excessAlcohol excess

Drugs Drugs (e.g. glucocorticoids, anticonvulsions)(e.g. glucocorticoids, anticonvulsions)

Modifiable (Endogenous)Modifiable (Endogenous) EndocrineEndocrine (estrogen or androgen deficiency, hyperthyroidism) (estrogen or androgen deficiency, hyperthyroidism)

Chronic diseasesChronic diseases (gastrectomy, cirrhosis, rheumatoid arthritis) (gastrectomy, cirrhosis, rheumatoid arthritis)

Paget’s diseasePaget’s disease

A common disorder of the bone.A common disorder of the bone.

Affecting up to 5% of the population over 55 years Affecting up to 5% of the population over 55 years old in the UK.old in the UK.

Bone turnover Bone turnover , with disordered bone remodeling., with disordered bone remodeling.

Plasma [calcium] and [phosphate] are usually Plasma [calcium] and [phosphate] are usually normal, although hypercalcemia can develop, normal, although hypercalcemia can develop, especially as a result of immobilization. especially as a result of immobilization.

bone turnover bone turnover plasma ALP activity and plasma ALP activity and indices indices of osteoclast activity.of osteoclast activity.

Renal osteodystrophyRenal osteodystrophy

ineffective conversion of 25-HCC to 1: 25-DHCC due to ineffective conversion of 25-HCC to 1: 25-DHCC due to loss of renal 1α-hydroxylase. loss of renal 1α-hydroxylase.

Causes defective calcium absorption and Causes defective calcium absorption and osteomalacia in adults, or rickets in children.osteomalacia in adults, or rickets in children.

May be corrected by treatment with 1α-HCC or 1:25-May be corrected by treatment with 1α-HCC or 1:25-DHCC.DHCC.

The pathophysiology of renal osteodystrophy is The pathophysiology of renal osteodystrophy is complex.complex.

The bone changes derived from one or more of the The bone changes derived from one or more of the following mechanisms:following mechanisms:

1. Vitamin D metabolism1. Vitamin D metabolism::

22 . .Phosphate retentionPhosphate retention::

plasma [phosphate],plasma [phosphate], combined with defective calcium combined with defective calcium absorption absorption plasma [Ca plasma [Ca2+2+] ] secondary secondary hyperparathyroidism hyperparathyroidism restore plasma [phosphate] and restore plasma [phosphate] and plasma [calcium], towards normal. plasma [calcium], towards normal.

Phosphate retentionPhosphate retention inhibit the renal 1α-hydroxylase. inhibit the renal 1α-hydroxylase.

Osteitis fibrosaOsteitis fibrosa, if it develops, may require , if it develops, may require parathyroidectomy.parathyroidectomy.

33 . .Phosphate bindersPhosphate binders : :

Oral phosphate bindersOral phosphate binders, usually , usually aluminium hydroxidealuminium hydroxide is used for treatment of patients with progressive is used for treatment of patients with progressive renal disease if secondary hyperparathyroidism failed renal disease if secondary hyperparathyroidism failed to maintain normal plasma [phosphate] .to maintain normal plasma [phosphate] .

Excess absorption of aluminiumExcess absorption of aluminium osteomalacia and osteomalacia and dialysis dementia. dialysis dementia.

Plasma [aluminium]Plasma [aluminium] should be measured periodically. should be measured periodically.

44 . . Dialysis fluid compositionDialysis fluid composition : :

The fluid [calcium] must be carefully controlledThe fluid [calcium] must be carefully controlled; ; – If it is too low If it is too low osteoporosis. osteoporosis. – If it is too high If it is too high extra skeletal calcification. extra skeletal calcification.

Dialysis fluid [aluminium] Dialysis fluid [aluminium] should beshould be sufficiently sufficiently low. low.

Plasma Plasma creatininecreatinine, , ureaurea, , NaNa++ KK++,, total COtotal CO22,,

albuminalbumin, [, [calcium]calcium] & [ & [phosphatephosphate] and ] and ALP ALP activity should all be measured regularly. activity should all be measured regularly.

Phosphate metabolismPhosphate metabolism

85 % of body phosphorus is located in bone. 85 % of body phosphorus is located in bone.

15 % is intracellular as phosphate compounds.15 % is intracellular as phosphate compounds.

In ECF, phosphate is mostly inorganicIn ECF, phosphate is mostly inorganic, as a mixture , as a mixture of HPOof HPO44

2-2- and H and H22POPO4-4- at physiological pH. at physiological pH.

Intracellular phosphate is largely organicIntracellular phosphate is largely organic as a as a component of phospholipids, phosphoproteins, component of phospholipids, phosphoproteins, nucleic acids and nucleotides, ( ATP). nucleic acids and nucleotides, ( ATP).

Macromolecular structure (DNA)Macromolecular structure (DNA)Energy metabolism (ATP).Energy metabolism (ATP).Cell signaling Cell signaling Enzyme activation by phosphorylation.Enzyme activation by phosphorylation.

Intracellular phosphate Intracellular phosphate has vital functions inhas vital functions in::

Hypo- and hyperphosphatemiaHypo- and hyperphosphatemia

Phosphate and calcium Phosphate and calcium homeostasis are linked.homeostasis are linked.

A plasma [phosphate] below A plasma [phosphate] below 0.4 mmol/L 0.4 mmol/L widespread cell widespread cell dysfunction and even death. dysfunction and even death.

Muscle pain and weakness, Muscle pain and weakness, including respiratory muscle including respiratory muscle weakness, associated with weakness, associated with CK are possibleCK are possible

Urgent phosphate Urgent phosphate supplementationsupplementation is requiredis required in hypophosphatemia.in hypophosphatemia.

Dietary deficiency is unusualDietary deficiency is unusual (phosphate occurs widely in (phosphate occurs widely in food)food)

Antacids may bind phosphate.Antacids may bind phosphate.

Metabolic and respiratory Metabolic and respiratory acidosisacidosis phosphate movement phosphate movement into the cell.into the cell.

Hypophosphatemia in DKA may Hypophosphatemia in DKA may be worsened when insulin is be worsened when insulin is administeredadministered (insulin promotes (insulin promotes cellular uptake of glucose and cellular uptake of glucose and phosphate).phosphate).

Cellular utilization of phosphate Cellular utilization of phosphate during re-feeding starved patients during re-feeding starved patients serious serious hypophosphatemia.hypophosphatemia.

Overview of Phosphate BalanceOverview of Phosphate Balance

Causes of hyperphosphatemia and Causes of hyperphosphatemia and hypophosphatemiahypophosphatemia

HyperphosphatemiaHyperphosphatemia HypophosphatemiaHypophosphatemia

intakeintake

excretionexcretion

RedistributionRedistribution

- IV therapy- IV therapy

- Phosphate enemas- Phosphate enemas

- Acute/chronic renal Acute/chronic renal failure failure

- Low PTH orLow PTH or

resistance to PTHresistance to PTH

- Vitamin D toxicity- Vitamin D toxicity

- Tumor lysis- Tumor lysis

- Rhabdomyolysis- Rhabdomyolysis

- Heat stroke- Heat stroke

intake/ intake/ absorptionabsorption

excretionexcretion

RedistributionRedistribution

- Vitamin D deficiency- Vitamin D deficiency

- Malabsorption- Malabsorption

- Oral phosphate binders- Oral phosphate binders

- Primary PTH excess- Primary PTH excess

- Secondary PTH excess - Secondary PTH excess (e.g. vit D deficiency)(e.g. vit D deficiency)

- Post-renal transplant- Post-renal transplant

- Re-feeding starved - Re-feeding starved patientspatients

- Hyperalimentation- Hyperalimentation

- Recovery from DKA- Recovery from DKA

- Alkalosis (respiratory)- Alkalosis (respiratory)

Etiologies of HyperphosphatemiaEtiologies of Hyperphosphatemia

Increased GI IntakeIncreased GI Intake- Fleet’s Phospho -Soda- Fleet’s Phospho -Soda

Decreased Urinary ExcretionDecreased Urinary Excretion- Renal Failure- Renal Failure- Low PTH (hypoparathyroidism)- Low PTH (hypoparathyroidism)

- thyroidectomy- I131 treatment for Graves disease of thyroid cancer- Autoimmune hypoparathyroidism

Cell Lysis- Rhabdomyolysis- Tumor lysis syndrome

Etiologies of HypophosphatemiaEtiologies of Hypophosphatemia

Decreased GI AbsorptionDecreased GI Absorption- Decreased dietary intake (rare in isolation)- Decreased dietary intake (rare in isolation)- Diarrhea / Malabsorption - Diarrhea / Malabsorption - Phosphate binders (calcium acetate, Al & Mg containing antacids)- Phosphate binders (calcium acetate, Al & Mg containing antacids)

Decreased Bone Resorption / Increased Bone MineralizationDecreased Bone Resorption / Increased Bone Mineralization

- Vitamin D deficiency / low calcitriol- Vitamin D deficiency / low calcitriol- Hungry bones syndrome- Hungry bones syndrome- Osteoblastic metastases- Osteoblastic metastases

Increased Urinary ExcretionIncreased Urinary Excretion- Elevated PTH (as in primary hyperparathyroidism)- Elevated PTH (as in primary hyperparathyroidism)- Vitamin D deficiency / low calcitriol- Vitamin D deficiency / low calcitriol- Fanconi’s syndrome- Fanconi’s syndrome

Internal Redistribution (due to acute stimulation of glycolysis)Internal Redistribution (due to acute stimulation of glycolysis)- Refeeding syndrome (seen in starvation, anorexia, and alcholism)- Refeeding syndrome (seen in starvation, anorexia, and alcholism)- During treatment for DKA- During treatment for DKA

Magnesium metabolismMagnesium metabolism

Mg is the second most Mg is the second most abundant intracellular cation.abundant intracellular cation.

Bone contains about 50% of Bone contains about 50% of the body’s magnesium.the body’s magnesium.

Small proportion of the body’s Small proportion of the body’s content is in the ECF.content is in the ECF.

Essential for the activity of Essential for the activity of many enzymes, including the many enzymes, including the phosphotransferases. phosphotransferases.

Normal dietary intake of Normal dietary intake of magnesium is about 12 mmol magnesium is about 12 mmol (300 mg) daily.(300 mg) daily.

Green vegetables, cereals and Green vegetables, cereals and meat are good sources.meat are good sources.

Significant amounts are Significant amounts are contained in gastric and biliary contained in gastric and biliary secretions. secretions.

Absorbed by active transport Absorbed by active transport across the intestinal mucosa by across the intestinal mucosa by a process involving vit. D. a process involving vit. D.

Renal conservation of Renal conservation of magnesium is partly controlled magnesium is partly controlled by PTH and aldosterone. by PTH and aldosterone.

Hypomagnesemia and Hypomagnesemia and magnesium deficiencymagnesium deficiency

Rarely occurs as an isolated phenomenon. Rarely occurs as an isolated phenomenon.

Usually accompanied byUsually accompanied by : : disorders of potassium, disorders of potassium, calcium and phosphorus metabolism.calcium and phosphorus metabolism.

Magnesium deficiency Magnesium deficiency should be suspected in should be suspected in patients with idiopathic hypocalcemia and /or patients with idiopathic hypocalcemia and /or hypokalemiahypokalemia

Muscular weakness,Muscular weakness, sometimes accompanied by sometimes accompanied by tetanytetany Cardiac arrhythmiasCardiac arrhythmias CNS abnormalitiesCNS abnormalities ((convulsions) .convulsions) .

Magnesium deficiencyMagnesium deficiency

Magnesium deficiencyMagnesium deficiency

CausesCauses ExamplesExamples

Abnormal lossesAbnormal losses - GI tract- GI tract

Urinary tractUrinary tract- - Renal diseaseRenal disease

- - ExtrarenalExtrarenal

Reduced intakeReduced intake

Mixed etiologyMixed etiology

- Prolonged aspiration, persistent diarrhea, - Prolonged aspiration, persistent diarrhea,

- Malabsorptive disease, fistula, jejuno-ileal by-pass, - - Malabsorptive disease, fistula, jejuno-ileal by-pass, - Small-bowel resectionSmall-bowel resection

- Renal tubular acidosis, chronic pyelonephritis, Renal tubular acidosis, chronic pyelonephritis, - HydronephrosisHydronephrosis- Conditions that modify renal function (e.g. primary Conditions that modify renal function (e.g. primary and secondary hyperaldosteronism, diuretics, and secondary hyperaldosteronism, diuretics, osmotic diuresisosmotic diuresis

- Conditions affecting transfer of magnesium from Conditions affecting transfer of magnesium from cells to bone e.g. tertiary hyperparathyroidism, cells to bone e.g. tertiary hyperparathyroidism, ketoacidosisketoacidosis

- If severe and prolonged, protein-energy malnutrition If severe and prolonged, protein-energy malnutrition - Chronic alcoholism, hepatic cirrhosis- Chronic alcoholism, hepatic cirrhosis

Plasma [magnesium] is usually < 0.5 mmol/L.Plasma [magnesium] is usually < 0.5 mmol/L.

Other tests (e.g. erythrocyte [MgOther tests (e.g. erythrocyte [Mg2+2+], muscle [Mg], muscle [Mg2+2+], ], magnesium loading tests) should be done.magnesium loading tests) should be done.

No general agreement on the best test to use. No general agreement on the best test to use.

Measurement of Urinary excretion of magnesium is Measurement of Urinary excretion of magnesium is easy and useful in distinguishing renal losses of easy and useful in distinguishing renal losses of magnesium from the other causes of hypomagnesemia.magnesium from the other causes of hypomagnesemia.

Renal excretion of magnesium often Renal excretion of magnesium often below below 0.5 mmol/24h in non-renal causes of magnesium 0.5 mmol/24h in non-renal causes of magnesium deficiency.deficiency.

HypermagnesemiaHypermagnesemia

most often due to:most often due to:– acute renal failure acute renal failure – advanced stages of chronic renal failure.advanced stages of chronic renal failure.

confirmed by measuring plasma [magnesium].confirmed by measuring plasma [magnesium].

Adrenocortical hypofunctionAdrenocortical hypofunction a slight a slight in plasma in plasma [magnesium].[magnesium].

Hypermagnesemia due to IV injection of magnesium saltsHypermagnesemia due to IV injection of magnesium salts is is rarerare..

nausea and vomiting, nausea and vomiting, weaknessweakness impaired consciousnessimpaired consciousness

If plasma [magnesium]If plasma [magnesium] exceeds 3.0 mmol/Lexceeds 3.0 mmol/L