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ENDOCRINE
PATHOPHYSIOLOGY
5., Metabolic
Bone
Diseases
Calcium
and Bone
Metabolism
Calcium Pools and Balance
Distribution of Calcium in Plasma
Calculation of Serum Total Calcium
Concentration
Albumin < 40 g/L
Cacorr=[Ca]T+0.02(40-[Alb])
w. HCO3-, citrate,
phosphate
pH  [Ca2+]
Albumin > 40 g/L
Cacorr=[Ca]T-0.02([Alb]-45)
Action of Major Calcium-regulating
Hormones
Bone
Kidney
Intestine
Parathhyroid
hormone
(PTH)
Ca2+, PO43reabsorption
Ca2+ reabsorption
PO43- reabsorption
HCO3- reabsorption,
1-OH-ase act.
No direct effect
Calcitonin
(CT)
Ca2+, PO43reabsorption
Ca2+, PO43reabsorption
No direct effect
Vitamin D
(1,25(OH)2D3)
Maintains
Ca2+ transport
system
Ca2+reabsorption
Ca2+, PO43- reabsorption
Parathyroid Glands
Formation of Active Vitamin D
Hypoparathyroidism
Etiology



Surgical Hypoparathyroidism
Idiopathic
Hypoparathyroidism
multi endocrine deficiencyautoimmune-candidiasis
(MEDAC)
Functional
Hypoparathyroidism
(low magnesium intake,
malabsorption)
Clinical Features
 Neuromusclar Manifestation




Paresthesias (numbness, tingling)
Hyperventilation
Adrenergic symptoms (increased epinephrine)
Signs of latent tetany
Chvostek`s sign
Trousseau`s sign
 Other Clinical Manifestation


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Posterior lenticular cataract
Cardiac manifestation
Dental manifestation
Malabsorption syndrome
Hypocalcemic States
Pseudohypoparathyroidism
Resistance of Target Hormone to PTH
Type I
Type II
PTH stimulation  no cAMP or phosphate
PTH stimulation  cAMP normal, no phosphate
Clinical Features
 Same as in hypoparathyroidism
 Mental retardation, short and stocky, obese
with rounded faces
 Short metacarpal or metatarsal bones short
fingers
 Delayed dentations, defective enamel and
absence of teeth
Pseudohypoparathyroidism
Primary Hyperparathyroidism
 Hyperplastic (about 20%), adenomatous (80%) or
malignant parathyroid gland
 Increased resorption of bone surfaces Increased
number of osteoclasts, osteocytic osteolysis
 Nephrolithiasis (20-30%), frequently complicated
with pyelonephritis
 Soft tissue calcification (lung, heart)
 Myopathy, neuropathic atrophy
Primary Hyperparathyroidism
 Features
 Uncontrolled secretion of PTH of the parathyroid gland
 Hypercalcemia fails to inhibit gland activity
 Nephrolithiasis, osteitis fibrosa, soft tissue calcification
(rare today)
 Etiology (unknown)
 Genetic factor may be involved
(autosomal dominant trait)
 Failure of feedback regulation
Primary Hyperparathyroidism
Hypercalcemia and Associated Hypercalciuria
Clinical Features
 Central nervous system


 Renal
 impaired mentation
 loss of memory for recent events
 emotional labiality
 depression etc.
Neuromusclar

 weakness (proximal musculature)
Rheumatologic
 joint pain

 polyuria
 nocturia
 nephrocalcinosis
 renal colic due to lithiasis
Gastrointestinal
 anorexia
 nausea
 vomiting
 dyspepsia
Dermatologic
 pruritus
Primary Hyperparathyroidism
Secondary Hyperparathyroidism
Chronic hypocalcemia  secondary hyperparathyroidism
 Chronic renal failure (most important)
 Dietary deficiency of vitamin D or calcium
 Decreased intestinal absorption of vitamin D
 Drugs that cause rickets or osteomalacia
(phenytoin, phenobarbital etc.)
 Excessive intake of inorganic phosphate compound
 Pseudohypoparathyroidism
 Severe hypomagnesemia
Secondary Hyperparathyroidism
Disorders of Calcitonin Secretion
No disorders has been reported to date in which
hypocalcitoninemia plays a definitive role
Hypercalcitoninema
 Medullary carcinoma of the thyroid gland
 Excess secretion of CT
 Multi Endocrine Neoplasia Syndrome (MEN)
 Clinical symptoms vary


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
asymptomatic thyroid mass
paraneoplastic syndromes (eg. Cushing`s syndrome)
diarrhea
flushing
family history
ENDOCRINE
PATHOPHYSIOLOGY
Metabolic Bone Diseases
Metabolic Bone Disease I.
Function of Bone
 Provide rigid support to extremities and body cavities


containing vital organs
Crucial to locomotion and provide efficient levers and sites
of attachment for muscle
Large reservoir of ions such as
calcium, phosphorus, magnesium etc.
Structure of Bone
 Cortical bone (densely packed)

Disorders lead to fractures of the long bones
Trabecular (cancellous) bone (spongy)
Disorders lead to vertebral fractures
Metabolic Bone Disease II.
Bone minerals
 Hydroxyapatite
 Amorphous calcium phosphate
Dynamics of Bone
 “Modeling”  formation of macroscopic skeleton
 “remodeling”  process occurring at bone surface
before and after adult development
Required to maintain the structure
and integrity of bone
Abnormality of “remodeling” are responsible
for metabolic bone disease
Bone Remodeling Cycle
Regulation of Bone Mass
Attainment of Maximal Bone Mass
Loss of Bone Mass by Age
Model of Risk Factors
Age-related
factors
Initial
bone mass
Menopause
BONE LOSS
low
bone mass
FRACTURES
Sporadic
factors
Propensity
to fall
trauma
Decreased
resistance to
trauma
ENDOCRINE
PATHOPHYSIOLOGY
Osteoporosis
Osteoporosis
A generalized bone disorder. Characterized by a decrease in the
quantity of bone but no change in its quality
Classification


Primary
 Idiopathic juvenile osteoporosis
 Idiopathic osteoporosis in young adults
 Involutional osteoporosis
Type I
“postmenopausal” osteoporosis
Type II
“senile” osteoporosis
Type III
osteoporosis associated with increased
parathyroid function
Secondary
 Hypercortisolism
 Hypogonadism
 Hyperthyroidism
 Diabetes mellitus
 Malabsorption syndrome
 Connective tissue disease etc.
Risk Factors and complicating Factors in
osteoporosis
 Genetic factors
 Nutritional deficiency
 Hypogonadism
 Drugs
 Smoking
 Renal disease
 Gastrointestinal disease
 non-black race
 Northern European
stock
 small bone mass
 alcohol
 corticosteroids
 thyroid hormones
 caffeine
 calcium, phosphate
 vitamin D, vitamin C
protein
Characterization of Involutional Osteoporosis
Type I
Type II
Age (yr)
Sex ratio (F:M)
Type of bone
51-75
6:1
trabecular
Rate of bone loss
accelerated
>70
2:1
trabecular and
cortical
not accelerated
Fracture site
Parathyroid function
vertebrae (crush) vertebrae and hip
and distal radius
decreased
increased
Calcium absorption
decreased
decreased
25(OH)D  1,25(OH)2D3
Conversion
secondary
decrease
primary
decrease
Pathogenesis of Type I osteoporosis
Other
factors
Estrogen
deficiency
Bone loss
Decreased
PTH
secretion
Decreased
1,25(OH)2D3
formation
Decreased
calcium
absorption
Pathogenesis of Type II osteoporosis
Aging
Decreased Bone
function
Decreased
1 OH-ase activity
(cellular level)
Decreased Ca absorption
Secondary Hyperparathyroidism
BONE LOSS
ENDOCRINE
PATHOPHYSIOLOGY
Osteomalatia and Rickets
Osteomalacia
Etiology



Vitamin D deficiency
 inadequate sunlight w/o
supplementation
 gastrointestinal disease
 impaired synthesis of 1,25(OH) D3
by the kidney
 target cell resistance to vitamin D3
Phosphate deficiency
 dietary
 impaired renal tubular
reabsorption
Primary mineralization defects
 osteopetrosis
 fibrogenesis imperfecta ossis

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Systemic acidosis
 chronic renal failure
 distal renal tubular
acidosis
Drug induced osteomalacia
 excessive fluoride
Toxin induced osteomalacia
 Aluminum, lead,
cadmium etc.
Osteomalacia
Laboratory Findings
 Depend upon the stages of disease
 Low level of 25(OH) D3
 Increased serum level of alkaline phosphatase
 Increased PTH
Differetial Diagnosis
 Hypophosphatemia
 normal Ca, PTH, 25(OH)D3
 Hypoparathyroidism
 hypophosphatemia, low level of PTH
 Tumor
Osteomalacia
Osteomalacia
Milk-Alkaline Syndrome
ENDOCRINE
PATHOPHYSIOLOGY
Disturbances in Sexual Function
Sexual Differentiation
Gametes
Gametes
Zygote
X+22 + X+22
X+22 + Y+22
Gonad
Bipotential
XX
Normal ovary
Bipotential
XY
Normal testes
Leyding cells
Phenotypic
Female sex
sex
differentiation
Testosterone DHT
Sertoli cells
Mullerian duct
inhibitory factor
External genitalia
Male sex
differentiation
Disorders of Gonadal Differentation
 Seminiferous tubule dysgenesis
(Klinefelter`s syndrome)
 Gonadal dysgenesis and its variants
(Turner`s syndrome)
 Complete and incomplete form to XX and XY
gonadal dysgenesis
 True hermaphroditism
Seminiferous Tubule Dysgenesis
(Klinefelter`s syndrome)
Commonest forms pf primary hypogonadism and infertility in male
Karyotype:
XXY
(XY/XXY; XXYY; XXXY and XXXYY)
(XXXXY, XX male H-Y antigen positive)
Clinical symptoms:
 Gynecomastia
 Diminished facial and body hair
 Small phallus, poor muscular development
 Eunochoid tall body habits
 Increased incidence of:
 mild diabetes mellitus
 varicose veins
 chronic pulmonary disease
 carcinoma of breast
 Progressive testicular lesion
Seminiferous Tubule Dysgenesis
(Klinefelter`s syndrome)
Syndrome of Gonadal Dysgenesis
(Turner`s syndrome)
 Karyotype: XO (XY/XO mosaicism; XO/XY; XO/XXY; XO/XY/XYY)
 Clinical features:
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Sexual infantilism
Short stature
Lymphedema of the extremities
Typical face
Short neck, shieldlike chest
Coarctation of the aorta
Hypertension, renal abnormalities
Obesity, diabetes mellitus, Hashimoto`s thyroiditis,
rheumatoid arthiritis etc.
Syndrome of Gonadal Dysgenesis
(Turner`s syndrome)
Pseudohermaphroidism
Female
Normal ovaries, extragonadal hypersecretion of
androgen
Masculinization, clitoral hypertrophy
Male
Testes, genital ducts or extragenitalias
are not completely masculinized
Deficient testosterone secretion
 failure of testicular differentiation
 failure of secretion of testosterone or Mullerian duct
inhibitory factors
 failure of target tissue response to testosterone or DHT
 Failure of conversion of testosterone to DHT
True Hermaphroditism
Clinical features
 uterus
 ovotestis
 karyotype
 breast development
 menses (50 %)
60 % XX
20 % XY
20 % XX/XY
Cause of true hermaphroditism
 sexchromatin mosaicism or chimerism
 Y to autosome; Y to X chromosome translocation or
exchange
 autosomal mutant gene