ENDOCRINEENDOCRINEPATHOPHYSIOLOGYPATHOPHYSIOLOGY

5., Metabolic Bone DiseasesCalcium and Bone MetabolismCalcium and Bone Metabolism

Calcium Pools and BalanceCalcium Pools and Balance

Distribution of Calcium in PlasmaDistribution of Calcium in Plasma

pH [Ca2+]

w. HCO3-, citrate,

phosphate

Calculation of Serum Total Calcium Calculation of Serum Total Calcium ConcentrationConcentration

Albumin < 40 g/LAlbumin < 40 g/L

CaCacorrcorr=[Ca]=[Ca]TT+0.02+0.02(40-[Alb])(40-[Alb])

Albumin > 40 g/LAlbumin > 40 g/L

CaCacorrcorr=[Ca]=[Ca]TT-0.02-0.02([Alb]-45)([Alb]-45)

Action of Major Calcium-regulating Action of Major Calcium-regulating HormonesHormones

BoneBone KidneyKidney IntestineIntestine

Parathhyroid Parathhyroid hormone hormone (PTH)(PTH)

Calcitonin Calcitonin (CT)(CT)

Vitamin D Vitamin D (1,25(OH)(1,25(OH)22DD33))

CaCa2+2+, PO, PO443-3-

reabsorptireabsorptionon

CaCa2+2+, PO, PO443-3-

reabsorptireabsorptionon

Maintains Maintains CaCa2+2+ transport transport systemsystem

CaCa2+2+ reabsorptionreabsorption POPO44

3- 3-

reabsorptionreabsorption HCOHCO33

- -

reabsorptionreabsorption, 1-, 1-OH-ase act.OH-ase act.

CaCa2+2+, PO, PO443-3-

reabsorptionreabsorption

CaCa2+2+reabsorptionreabsorption

No direct effectNo direct effect

No direct effectNo direct effect

CaCa2+2+, PO, PO443-3-

reabsorptionreabsorption

Parathyroid GlandsParathyroid Glands

Formation of Active Vitamin DFormation of Active Vitamin D

HypoparathyroidismHypoparathyroidism

EtiologyEtiology Surgical HypoparathyroidismSurgical Hypoparathyroidism Idiopathic Idiopathic

Hypoparathyroidism Hypoparathyroidism

multi endocrine deficiency-multi endocrine deficiency-autoimmune-candidiasis autoimmune-candidiasis (MEDAC)(MEDAC)

Functional Functional HypoparathyroidismHypoparathyroidism

(low magnesium intake, (low magnesium intake, malabsorption)malabsorption)

Clinical FeaturesClinical Features

Neuromusclar ManifestationNeuromusclar Manifestation Paresthesias (numbness, tingling)Paresthesias (numbness, tingling) HyperventilationHyperventilation Adrenergic symptoms (increased Adrenergic symptoms (increased

epinephrine)epinephrine) Signs of latent tetanySigns of latent tetany

Chvostek`s signChvostek`s signTrousseau`s signTrousseau`s sign

Other Clinical ManifestationOther Clinical Manifestation Posterior lenticular cataractPosterior lenticular cataract Cardiac manifestationCardiac manifestation Dental manifestationDental manifestation Malabsorption syndromeMalabsorption syndrome

Hypocalcemic StatesHypocalcemic States

PseudohypoparathyroidismPseudohypoparathyroidism

Same as in hypoparathyroidismSame as in hypoparathyroidism Mental retardation, short and Mental retardation, short and

stocky, obese with rounded facesstocky, obese with rounded faces Short metacarpal or metatarsal Short metacarpal or metatarsal

bones short fingersbones short fingers Delayed dentations, defective Delayed dentations, defective

enamel and absence of teethenamel and absence of teeth

Clinical FeaturesClinical Features

Resistance of Target Hormone to PTH

Type IType I PTH stimulation PTH stimulation no cAMP or phosphate no cAMP or phosphateType IIType II PTH stimulation PTH stimulation cAMP normal, no phosphate cAMP normal, no phosphate

PseudohypoparathyroidismPseudohypoparathyroidism

Hyperplastic (about 20%), adenomatous (80%) or Hyperplastic (about 20%), adenomatous (80%) or malignant parathyroid glandmalignant parathyroid gland

Increased resorption of bone surfaces Increased Increased resorption of bone surfaces Increased number of osteoclasts, osteocytic osteolysisnumber of osteoclasts, osteocytic osteolysis

Nephrolithiasis (20-30%), frequently complicated Nephrolithiasis (20-30%), frequently complicated with pyelonephritiswith pyelonephritis

Soft tissue calcification (lung, heart)Soft tissue calcification (lung, heart)

Myopathy, neuropathic atrophyMyopathy, neuropathic atrophy

Primary HyperparathyroidismPrimary Hyperparathyroidism

Primary HyperparathyroidismPrimary Hyperparathyroidism

FeaturesFeatures Uncontrolled secretion of PTH of the Uncontrolled secretion of PTH of the

parathyroid glandparathyroid gland Hypercalcemia fails to inhibit gland activityHypercalcemia fails to inhibit gland activity Nephrolithiasis, osteitis fibrosa, soft tissue Nephrolithiasis, osteitis fibrosa, soft tissue

calcification (rare today)calcification (rare today)

EtiologyEtiology (unknown)(unknown) Genetic factor may be involvedGenetic factor may be involved

(autosomal dominant trait)(autosomal dominant trait)

Failure of feedback regulationFailure of feedback regulation

Primary HyperparathyroidismPrimary Hyperparathyroidism

Clinical FeaturesClinical Features

Central nervous systemCentral nervous system impaired mentationimpaired mentation loss of memory for recent eventsloss of memory for recent events emotional labialityemotional labiality depression etc.depression etc.

NeuromusclarNeuromusclar weakness weakness (proximal musculature)(proximal musculature)

RheumatologicRheumatologic joint painjoint pain

Hypercalcemia and Associated HypercalciuriaHypercalcemia and Associated Hypercalciuria

RenalRenal polyuriapolyuria nocturianocturia nephrocalcinosisnephrocalcinosis renal colic due to lithiasisrenal colic due to lithiasis

GastrointestinalGastrointestinal anorexiaanorexia nauseanausea vomitingvomiting dyspepsiadyspepsia

DermatologicDermatologic prurituspruritus

Primary HyperparathyroidismPrimary Hyperparathyroidism

Secondary HyperparathyroidismSecondary Hyperparathyroidism

Chronic renal failure Chronic renal failure (most important)(most important)

Dietary deficiency of vitamin D or calciumDietary deficiency of vitamin D or calcium

Decreased intestinal absorption of vitamin DDecreased intestinal absorption of vitamin D

Drugs that cause rickets or osteomalaciaDrugs that cause rickets or osteomalacia

(phenytoin, phenobarbital etc.)(phenytoin, phenobarbital etc.)

Excessive intake of inorganic phosphate compoundExcessive intake of inorganic phosphate compound

PseudohypoparathyroidismPseudohypoparathyroidism

Severe hypomagnesemiaSevere hypomagnesemia

Chronic hypocalcemia Chronic hypocalcemia secondary hyperparathyroidism secondary hyperparathyroidism

Secondary HyperparathyroidismSecondary Hyperparathyroidism

Disorders of Calcitonin SecretionDisorders of Calcitonin Secretion

Medullary carcinoma of the thyroid glandMedullary carcinoma of the thyroid gland

Excess secretion of CTExcess secretion of CT

Multi Endocrine Neoplasia Syndrome (MEN)Multi Endocrine Neoplasia Syndrome (MEN)

Clinical symptoms varyClinical symptoms vary asymptomatic thyroid massasymptomatic thyroid mass paraneoplastic syndromes (eg. Cushing`s syndrome)paraneoplastic syndromes (eg. Cushing`s syndrome) diarrheadiarrhea flushingflushing family historyfamily history

No disorders has been reported to date in which No disorders has been reported to date in which hypocalcitoninemia plays a definitive rolehypocalcitoninemia plays a definitive role

HypercalcitoninemaHypercalcitoninema

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Metabolic Bone DiseasesMetabolic Bone Diseases

Metabolic Bone Disease I.Metabolic Bone Disease I.

Provide rigid support to extremities and body cavities Provide rigid support to extremities and body cavities containing vital organscontaining vital organs

Crucial to locomotion and provide efficient levers and sites Crucial to locomotion and provide efficient levers and sites of attachment for muscleof attachment for muscle

Large reservoir of ions such asLarge reservoir of ions such as

calcium, phosphorus, magnesium etc.calcium, phosphorus, magnesium etc.

Cortical bone Cortical bone (densely packed)(densely packed)

Disorders lead to fractures of the long bonesDisorders lead to fractures of the long bones

Trabecular (cancellous) bone Trabecular (cancellous) bone (spongy)(spongy)

Disorders lead to vertebral fracturesDisorders lead to vertebral fractures

Function of BoneFunction of Bone

Structure of BoneStructure of Bone

Metabolic Bone Disease II.Metabolic Bone Disease II.

HydroxyapatiteHydroxyapatite

Amorphous calcium phosphateAmorphous calcium phosphate

Bone mineralsBone minerals

““Modeling” Modeling” formation of macroscopic skeleton formation of macroscopic skeleton

““remodeling” remodeling” process occurring at bone surface process occurring at bone surface

before and after adult developmentbefore and after adult development

Required to maintain the structureRequired to maintain the structure

and integrity of boneand integrity of bone

Dynamics of BoneDynamics of Bone

Abnormality of “remodeling” are responsible Abnormality of “remodeling” are responsible for metabolic bone diseasefor metabolic bone disease

Bone Remodeling CycleBone Remodeling Cycle

Regulation of Bone MassRegulation of Bone Mass

Attainment of Maximal Bone MassAttainment of Maximal Bone Mass

Loss of Bone Mass by AgeLoss of Bone Mass by Age

ModelModel of Risk Factors of Risk Factors

Age-relatedAge-relatedfactorsfactors

MenopauseMenopause

SporadicSporadicfactorsfactors

InitialInitialbone massbone mass

lowlowbone massbone mass

BONE LOSSBONE LOSS

PropensityPropensityto fallto fall

DecreasedDecreasedresistance toresistance to

traumatrauma

traumatrauma

FRACTURESFRACTURES

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OsteoporosisOsteoporosis

OsteoporosisOsteoporosis

PrimaryPrimary Idiopathic juvenile osteoporosisIdiopathic juvenile osteoporosis Idiopathic osteoporosis in young adultsIdiopathic osteoporosis in young adults Involutional osteoporosisInvolutional osteoporosis

Type IType I “postmenopausal” osteoporosis“postmenopausal” osteoporosisType IIType II “senile” osteoporosis“senile” osteoporosisType IIIType III osteoporosis associated with osteoporosis associated with

increased increased parathyroid functionparathyroid function SecondarySecondary

HypercortisolismHypercortisolism HypogonadismHypogonadism HyperthyroidismHyperthyroidism Diabetes mellitusDiabetes mellitus Malabsorption syndromeMalabsorption syndrome Connective tissue disease etc.Connective tissue disease etc.

A generalized bone disorder. Characterized by a decrease in the A generalized bone disorder. Characterized by a decrease in the quantity of bone but no change in its qualityquantity of bone but no change in its quality

ClassificationClassification

Risk Factors and complicating Factors in Risk Factors and complicating Factors in osteoporosis osteoporosis

Genetic factorsGenetic factors non-black racenon-black race Northern European Northern European

stockstock small bone masssmall bone mass

HypogonadismHypogonadism DrugsDrugs

alcoholalcohol corticosteroidscorticosteroids thyroid hormonesthyroid hormones caffeinecaffeine

Nutritional deficiencyNutritional deficiency calcium, phosphatecalcium, phosphate vitamin D, vitamin Cvitamin D, vitamin C proteinprotein

SmokingSmoking Renal diseaseRenal disease Gastrointestinal diseaseGastrointestinal disease

Characterization of Involutional OsteoporosisCharacterization of Involutional Osteoporosis

Age (yr)Age (yr) 51-7551-75 >70>70Sex ratio (F:M)Sex ratio (F:M) 6:16:1 2:1 2:1Type of boneType of bone trabeculartrabecular trabecular and trabecular and

corticalcorticalRate of bone lossRate of bone loss acceleratedaccelerated not accelerated not accelerated

Fracture siteFracture site vertebrae (crush)vertebrae (crush) vertebrae and hipvertebrae and hip and distal radiusand distal radius

Parathyroid function Parathyroid function decreaseddecreased increased increased

Calcium absorptionCalcium absorption decreaseddecreased decreased decreased

25(OH)D 25(OH)D 1,25(OH) 1,25(OH)22DD33 secondarysecondary primaryprimaryConversionConversion decreasedecrease decreasedecrease

Type IType I Type II Type II

Pathogenesis of Type I osteoporosisPathogenesis of Type I osteoporosis

EstrogenEstrogendeficiencydeficiency

DecreasedDecreasedPTHPTH

secretionsecretion

DecreasedDecreasedcalciumcalcium

absorptionabsorption

DecreasedDecreased1,25(OH)1,25(OH)22DD33

formationformation

OtherOtherfactorsfactors

Bone loss

Pathogenesis of Type II osteoporosisPathogenesis of Type II osteoporosis

Decreased BoneDecreased Bonefunctionfunction

(cellular level)(cellular level)

BONE LOSSBONE LOSS

Decreased Decreased 1 OH-ase activity1 OH-ase activity

Decreased Ca absorptionDecreased Ca absorption

Secondary HyperparathyroidismSecondary Hyperparathyroidism

AgingAging

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Osteomalatia and RicketsOsteomalatia and Rickets

OsteomalaciaOsteomalacia

Vitamin D deficiencyVitamin D deficiency inadequate sunlight w/o inadequate sunlight w/o

supplementationsupplementation gastrointestinal diseasegastrointestinal disease impaired synthesis of 1,25(OH) Dimpaired synthesis of 1,25(OH) D33 by by

the kidneythe kidney target cell resistance to vitamin Dtarget cell resistance to vitamin D33

Phosphate deficiencyPhosphate deficiency dietarydietary impaired renal tubular reabsorptionimpaired renal tubular reabsorption

Primary mineralization defectsPrimary mineralization defects osteopetrosisosteopetrosis fibrogenesis imperfecta ossisfibrogenesis imperfecta ossis

Systemic acidosisSystemic acidosis chronic renal failurechronic renal failure distal renal tubular distal renal tubular

acidosisacidosis

Drug induced osteomalaciaDrug induced osteomalacia excessive fluorideexcessive fluoride

Toxin induced osteomalaciaToxin induced osteomalacia Aluminum, lead, Aluminum, lead,

cadmium etc.cadmium etc.

EtiologyEtiology

OsteomalaciaOsteomalacia

Laboratory FindingsLaboratory Findings Depend upon the stages of diseaseDepend upon the stages of disease Low level of 25(OH) DLow level of 25(OH) D33

Increased serum level of alkaline phosphataseIncreased serum level of alkaline phosphatase Increased PTHIncreased PTH

Differetial DiagnosisDifferetial Diagnosis HypophosphatemiaHypophosphatemia

normal Ca, PTH, 25(OH)Dnormal Ca, PTH, 25(OH)D33

HypoparathyroidismHypoparathyroidism hypophosphatemia, low level of PTHhypophosphatemia, low level of PTH

TumorTumor

OsteomalaciaOsteomalacia

OsteomalaciaOsteomalacia

Milk-Alkaline SyndromeMilk-Alkaline Syndrome

ENDOCRINE ENDOCRINE PATHOPHYSIOLOGYPATHOPHYSIOLOGY

Disturbances in Sexual FunctionDisturbances in Sexual Function

Sexual DifferentiationSexual Differentiation

GametesGametes Gametes Gametes

Zygote Zygote X+22 + X+22X+22 + X+22 X+22 + Y+22 X+22 + Y+22

Gonad Gonad BipotentialBipotential Bipotential Bipotential

PhenotypicPhenotypicsexsex

Normal ovaryNormal ovary Normal testesNormal testes

Leyding cellsLeyding cells Sertoli cellsSertoli cellsMullerian duct Mullerian duct

inhibitory factorinhibitory factor

Male sex Male sex differentiationdifferentiation

XXXXXYXY

Female sexFemale sexdifferentiationdifferentiation External genitaliaExternal genitalia

Testosterone DHTTestosterone DHT

Disorders of Gonadal DifferentationDisorders of Gonadal Differentation

Seminiferous tubule dysgenesisSeminiferous tubule dysgenesis

(Klinefelter`s syndrome)(Klinefelter`s syndrome)

Gonadal dysgenesis and its variantsGonadal dysgenesis and its variants

(Turner`s syndrome)(Turner`s syndrome)

Complete and incomplete form to XX and XY Complete and incomplete form to XX and XY

gonadal dysgenesisgonadal dysgenesis

True hermaphroditismTrue hermaphroditism

Seminiferous Tubule DysgenesisSeminiferous Tubule Dysgenesis(Klinefelter`s syndrome)(Klinefelter`s syndrome)

Karyotype:Karyotype: XXYXXY (XY/XXY; XXYY; XXXY and XXXYY)(XY/XXY; XXYY; XXXY and XXXYY)(XXXXY, XX male H-Y antigen positive)(XXXXY, XX male H-Y antigen positive)

Clinical symptoms:Clinical symptoms: GynecomastiaGynecomastia Diminished facial and body hairDiminished facial and body hair Small phallus, poor muscular developmentSmall phallus, poor muscular development Eunochoid tall body habitsEunochoid tall body habits Increased incidence of:Increased incidence of:

mild diabetes mellitusmild diabetes mellitus varicose veinsvaricose veins chronic pulmonary diseasechronic pulmonary disease carcinoma of breastcarcinoma of breast

Progressive testicular lesionProgressive testicular lesion

Commonest forms pf primary hypogonadism and infertility in maleCommonest forms pf primary hypogonadism and infertility in male

Seminiferous Tubule DysgenesisSeminiferous Tubule Dysgenesis(Klinefelter`s syndrome)(Klinefelter`s syndrome)

Syndrome of Gonadal DysgenesisSyndrome of Gonadal Dysgenesis(Turner`s syndrome)(Turner`s syndrome)

Karyotype: Karyotype: XO (XY/XO mosaicism; XO/XY; XO/XXY; XO/XY/XYY)XO (XY/XO mosaicism; XO/XY; XO/XXY; XO/XY/XYY)

Clinical features:Clinical features: Sexual infantilismSexual infantilism Short statureShort stature Lymphedema of the extremitiesLymphedema of the extremities Typical faceTypical face Short neck, shieldlike chestShort neck, shieldlike chest Coarctation of the aortaCoarctation of the aorta Hypertension, renal abnormalitiesHypertension, renal abnormalities Obesity, diabetes mellitus, Hashimoto`s thyroiditis, rheumatoid Obesity, diabetes mellitus, Hashimoto`s thyroiditis, rheumatoid

arthiritis etc.arthiritis etc.

Syndrome of Gonadal DysgenesisSyndrome of Gonadal Dysgenesis(Turner`s syndrome)(Turner`s syndrome)

PseudohermaphroidismPseudohermaphroidism

FemaleFemaleNormal ovaries, extragonadal hypersecretion ofNormal ovaries, extragonadal hypersecretion ofandrogenandrogenMasculinization, clitoral hypertrophyMasculinization, clitoral hypertrophy

MaleMaleTestes, genital ducts or extragenitaliasTestes, genital ducts or extragenitaliasare not completely masculinizedare not completely masculinizedDeficient testosterone secretionDeficient testosterone secretion failure of testicular differentiationfailure of testicular differentiation failure of secretion of testosterone or Mullerian duct failure of secretion of testosterone or Mullerian duct

inhibitory factorsinhibitory factors failure of target tissue response to testosterone or DHTfailure of target tissue response to testosterone or DHT Failure of conversion of testosterone to DHTFailure of conversion of testosterone to DHT

True HermaphroditismTrue Hermaphroditism

Clinical featuresClinical features uterusuterus breast development breast development ovotestisovotestis menses (50 %) menses (50 %) karyotypekaryotype 60 % XX60 % XX

20 % XY20 % XY

20 % XX/XY20 % XX/XY

Cause of true hermaphroditismCause of true hermaphroditism sexchromatin mosaicism or chimerismsexchromatin mosaicism or chimerism Y to autosome; Y to X chromosome translocation or Y to autosome; Y to X chromosome translocation or

exchangeexchange autosomal mutant geneautosomal mutant gene