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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
ENDOCRINEENDOCRINEPATHOPHYSIOLOGYPATHOPHYSIOLOGY
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
ENDOCRINEENDOCRINEPATHOPHYSIOLOGYPATHOPHYSIOLOGY
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
ENDOCRINEENDOCRINEPATHOPHYSIOLOGYPATHOPHYSIOLOGY
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