OBJECTIVES



Identify the origin,target organs &
physiologic effects of parathyroid
hormone(including effects on vitamin D
metabolism)
Describe the regulation of parathyroid
hormone secretion & the role of the
calcium-sensing receptor.
Describe the cell of origin,the target
organs,the physiological effects & the
regulation of release of calcitonin.


Illustrate & discuss the physiological
response to hypocalcemia &
hypercalcemia.
Correlate this knowledge to clinical
conditions related to hypo &
hypersecretion of parathyroid hormones.
CALCIUM
METABOLISM
-
Dietary sources& requirement
Dietary sources of calcium: milk, milk
products,meat, fish, vegetables,
beans,
Daily requirements:
Adults: 800 mg TO 1 gm.
Pregnancy & lactation:1500mg
Children: 800-1200mg

CALCIUM METABOLISM

A total of 1-2 kg of calcium is in the body,
98% of it in the
skeleton. Some is bound to proteins,
another fraction is bound to
anions, usually citrate and phosphate, and
the rest is free or ionized
calcium. Clinically, the most significant is
the ionized fraction.
Plasma level

9 – 11 mg %,of this
4mg% non diffusible
6mg%diffusible
With plasm proteins
(not useful )
1mg%
5mg%
with bocarb Free ionised
& phosp
This free ionised form (50%of tot.is imp. For
Phyiological functios.
Calcium is present:
1.
Extra cellularly- which can not diffuse into cell
as-a). Cell membrane is impermeable to ca.
b).Presence of Ca ATPase pump,c).Ca-Na
exchange system.
2.
Intra cellularly: a. large fraction is stored as in
ER. b. Small fraction- free calcium- which
brings activity in cells
Intra cellular cal. Binding proteins: 1. calmodulin.
2. Calbindin. 3. Troponin.
Bone calcium



99% of total calcium is in bones.
A fraction of bone calcium can be
exchangeable with plasma calcium. It is of
2 types: Readily
exchangeable(smallfraction) and Slowly
exchageable ( bigger fraction).
The exchangeable bone calcium is under
the influence of PTH, 1,25 DHCC.
Calcium- Functions









Required for formation of bones& teeth.
muscle contraction
Nerve excitation, membrane excitation
NM & Synaptic transmission.
Glandular secretion
Blood coagulation
intracellular messenger systems
cardiac repolarization.
Milk formation.
Entry & exit of calcium
Amount ingested = excreted in
stool+ urine
CALCIUM PHYSIOLOGY:
BLOOD CALCIUM

CALCIUM FLUX INTO AND OUT OF BLOOD

“IN” FACTORS:



INTESTINAL ABSORPTION,
BONE RESORPTION
Renal reabsorption
“OUT” FACTORS: RENAL EXCRETION, BONE
FORMATION (Ca INCORPATION INTO BONE)
CALCIUM PHYSIOLOGY:
BLOOD CALCIUM

BLOOD CALCIUM IS TIGHTLY
REGULATED

PRINCIPLE ORGAN SYSTEMS


GUT, BONE, KIDNEYS
HORMONES
PARATHYROID HORMONE (PTH),
 1,25 DHCC(VITAMIN D) & Calcitonin


INTEGRATED PHYSIOLOGY OF ORGAN
SYSTEMS AND HORMONES MAINTAIN
BLOOD CALCIUM
Hormones of calcium metabolism
PARATHYROID HORMONE (PTH),
 1,25 DHCC(VITAMIN D)
 Calcitonin

Parathyroid glands

Were discovered in 1880 by Sandstorm of
Sweden
Parathyroid Hormone





Produced by Parathyroid Chief cells
Secreted in response to low iCa++
Stimulates renal conversion of 25-(OH)D3 to
1,25-(OH)2D which increases intestinal Ca++
absorption
Directly stimulates renal Ca++ absorption and
PO43- excretion
Stimulates osteoclastic resorption of bone
PARATHYROID HORMONE
(PTH) PHYSIOLOGY

PTH FUNCTIONS TO PRESERVE NORMAL BLOOD
CALCIUM (AND PHOSPHATE)
 PTH STIMULATES BONE RESORPTION AND, THUS,
INCREASES BLOOD CALCIUM
 PTH STIMULATES RENAL TUBULAR REABSORPTION
OF CALCIUM, AND THUS, INCREASES BLOOD
CALCIUM
 PTH STIMULATES RENAL 1a-HYDROXYLATION OF
25(OH)VITAMIN D, THUS INDIRECTLY STIMULATING
INTESTINAL ABSORPTION OF CALCIUM
PTH PHYSIOLOGY



PTH SECRETION IS INCREASED IN RESPONSE TO
FALLING CALCIUM LEVEL, TO HELP KEEP CALCIUM
NORMAL BY THE ABOVE MECHANISMS
RISING CALCIUM FEEDS BACK TO THE PARATHYROIDS
TO SUPPRESS PTH SECRETION IN A CLASSIC
ENDOCRINE FEEDBACK LOOP
THIS LOOP IS MUCH LIKE OTHER ENDOCRINE
FEEDBACK LOOPS YOU’RE FAMILIAR WITH SUCH AS
GLUCOSE AND INSULIN, THYROID HORMONE AND TSH,
ETC.
CALCIUM, PTH, AND VITAMIN D
FEEDBACK LOOPS
BONE RESORPTION
URINARY LOSS
SUPPRESS PTH
1,25(OH)2 D PRODUCTION
RISING BLOOD Ca
NORMAL BLOOD Ca
FALLING BLOOD Ca
BONE RESORPTION
URINARY LOSS
1,25(OH)2 D PRODUCTION
STIMULATE PTH
CALCIUM FEEDBACK TO
REGULATE PTH SECRETION



CALCIUM-SENSING RECEPTOR IN THE PARATHYROIDS
 7-TRANSMEMBRANE SPANNING PROTEIN RECEPTOR THAT
BINDS CALCIUM EXTRACELLULARLY, AND IS COUPLED TO
SIGNALLING PATHWAYS VIA G-PROTEINS
THE Ca-SENSING RECEPTOR IS ALSO PRESENT IN THE KIDNEYS,
AND A VARIETY OF OTHER TISSUES
MECHANISM OF CALCIUM FEEDBACK TO REGULATION OF PTH
SECRETION IS MEDIATED VIA THE Ca-SENSING RECEPTOR


INCREASING AMBIENT CALCIUM IS SENSED BY RECEPTOR AND
SUPPRESSES PTH SECRETION
FALLING AMBIENT CALCIUM IS SENSED BY RECEPTOR AND
STIMULATES PTH SECRETION
CALCIUM SENSING RECEPTOR:
CLINICOPATHOLOGIC
CORRELATES

INACTIVATING MUTATIONS RIGHT-SHIFT THE SETPOINT FOR PTH
SECRETION, SO THAT IT TAKES HIGHER CALCIUM TO SUPPRESS
PTH SECRETION
 IN THE HETEROZYGOUS STATE, IT TAKES HIGHER AMBIENT
CALCIUM TO SUPPRESS PTH SECRETION. PATIENTS WITH
THIS MUTATION HAVE HYPERCALCEMIA, AND RELATIVELY
LOW URINE CALCIUM LOSSES. THIS IS REFERRED TO AS
FAMILIAL BENIGN HYPOCALCIURIC HYPERCALCEMIA (FBHH).
IT IS A CONDITION FREE OF THE PROBLEMS USUALLY
ASSOCIATED WITH HYPERCALCEMIA.
 IN THE HOMOZYGOUS STATE, IT IS LETHAL IN INFANCY AS A
RESULT OF VERY SEVERE HYPERCALCEMIA.
PTH RECEPTOR

PTH RECEPTORS ARE TRANSMEMBRANE
PROTEIN RECEPTORS



FOUND IN A VARIETY OF TISSUES (BONE, KIDNEY, OTHERS).
PTH RECEPTORS ARE COUPLED TO SECOND MESSENGER SYSTEMS
VIA STIMULATORY G PROEINS (Gs). BINDING PTH TO THE RECEPTOR
CAUSES GDP TO DISSOCIATE FROM Gs AND GTP TO BIND. THE
SIGNAL IS THEN TRANSMITTED TO A VARIETY OF SECOND
MESSENGER SYSTEMS, RESULTING IN PRODUCTION OF CYCLIC AMP
(cAMP), INOSITOL TRIPHOSPHATE, DIACYLGLYCEROL, AND OTHERS.
THE PTH RECEPTOR ALSO BINDS THE PARATHYROID HORMONE
RELATED PROTEIN (PTHrP) WITH EQUAL AFFINITY TO PTH. FOR
THIS REASON, THE RECEPTOR IS USUALLY REFERRED TO AS THE
PTH/PTHrP RECEPTOR.
PTH RECEPTOR:
CLINICOPATHOLOGIC CORRELATES

THERE IS A FAMILY OF DISEASES KNOWN AS
PSEUDOHYPOPARATHYROIDISM.



CLINICAL MANIFESTATIONS INCLUDE HYPOCALCEMIA THUS MIMICKING
HYPOPARATHYROIDISM. HOWEVER, AFFECTED INDIVIDUALS ARE RESISTANT
TO PTH, NOT DEFICIENT IN PTH. PTH LEVELS ARE ELEVATED IN THESE
PATIENTS.
THE MOLECULAR DEFECTS IN PSEUDOHYPOPARATHYROIDISM ARE NOT ALL
CHARACTERIZED, ALTHOUGH IN SOME CASES ARE WELL CHARACTERIZED. A
CLASSIC EXAMPLE IS A MUTATION IN ONE OF THE SUBUNITS OF Gs, SO THAT
SIGNAL TRANSDUCTION UPON PTH BINDING THE RECEPTOR IS NOT
TRANSMITTED TO THE SECOND MESSENGER PATHWAYS
CONSIDER IN RELATION TO DISEASES OF INSULIN RESISTANCE, VITAMIN D
RESISTANCE, THYROID HORMONE RESISTANCE, ETC.
CALCIUM HOMEOSTASIS
DIETARY CALCIUM
THE ONLY “IN”
BONE
DIETARY HABITS,
SUPPLEMENTS
ORGAN,
ENDOCRINE
BLOOD CALCIUM
INTESTINAL ABSORPTION
ORGAN PHYSIOLOGY
KIDNEYS
ENDOCRINE PHYSIOLOGY
ORGAN PHYS.
ENDOCRINE PHYS.
URINE
THE PRINCIPLE “OUT”
VITAMIN D PHYSIOLOGY

VITAMIN D IS A HORMONE BY CLASSIC
CRITERIA: MADE IN ONE PLACE (OR
SEQUENTIALLY SEVERAL PLACES!), AND
ACTING IN OTHER PLACES. THIS
DISTINGUISHES IT FROM OTHER “CLASSIC”
VITAMINS, SUCH AS VITAMIN C, B VITAMINS,
ETC., WHICH ACT AS COFACTORS IN
BIOCHEMICAL REACTIONS.
Vitamin D

Sources



Metabolism



Food – Vitamin D2
UV light mediated cholesterol metabolism – D3
D2 and D3 are converted to 25(OH)-D by the liver
25(OH)-D is converted to 1,25(OH)2-D by the Kidney
Function


Stimulation of Osteoblasts
Increases GI absorption of dietary Ca++
VITAMIN D SYNTHESIS

THE PRECURSOR FOR VITAMIN D
SYNTHESIS IS A STEROL IN THE
CHOLESTEROL BIOSYNTHETIC
PATHWAY, 7-DEHYDROCHOLESTEROL.

IN THE SKIN, ULTRAVIOLET LIGHT
TRANSFORMS 7-DEHYDROCHOLESTEROL TO
VITAMIN D3

ROLE OF SUNLIGHT IN VITAMIN D ADEQUACY
VITAMIN D SYNTHESIS

VITAMIN D3 CIRCULATES TO THE LIVER, WHERE THE
ENZYME 25-HYDROXYLASE HYDROXYLATES IT TO 25HYDROXY VITAMIN D (25(OH)VITAMIN D)
 25-HYDROXYLASE FUNCTIONS CONSTITUTIVELY
WITHOUT INPUT FROM BLOOD CALCIUM STATUS OR
PTH
 25(OH)VITAMIN D IS THE BEST SCREENING TEST
FOR VITAMIN D ADEQUACY
VITAMIN D SYNSTHESIS

25(OH)VITAMIN D CIRCULATES TO THE KIDNEYS,
WHERE THE ENZYME RENAL 1a-HYDROXYLASE
HYDROXYLATES IT TO 1,25(OH)2 VITAMIN D
 THIS IS THE ACTIVE METABOLITE OF VITAMIN D.
1,25(OH)2 VITAMIN D MEDIATES THE PHYSIOLOGIC
ROLES OF VITAMIN D.
 RENAL 1a-HYDROXYLASE IS REGULATED BY PTH
WHICH STIMULATES ITS ACTIVITY. PTH IS THE
PRINCIPLE PHYSIOLOGIC REGULATOR, ALTHOUGH
CALCIUM CAN AFFECT THE ACTIVITY.
VITAMIN D SYNTHESIS
SKIN
LIVER
7-DEHYDROCHOLESTEROL
h
VITAMIN D3
VITAMIN D3
KIDNEY
25(OH)VITAMIN D
25-HYDROXYLASE
25(OH)VITAMIN D
1a-HYDROXYLASE
1,25(OH)2 VITAMIN D
(ACTIVE METABOLITE)
TISSUE-SPECIFIC VITAMIN D RESPONSES
VITAMIN D

THE BODY CAN SUPPLY ITS OWN
VITAMIN D VIA THE SYNTHETIC
PATHWAYS SHOWN ABOVE.
ALTERNATIVELY, VITAMIN D MAY BE
SUPPLIED BY VITAMIN D - ENRICHED
FOODS. THE CLASSIC EXAMPLES ARE
MILK AND MULTIPLE VITAMINS.
VITAMIN D MECHANISM OF ACTION:
VITAMIN D RECEPTOR


BIOLOGICAL EVOLUTION IS VERY CONSERVATIVE.
VITAMIN D SHARES MANY SIMILARITIES WITH
STEROID HORMONES. IT IS NOT SURPRISING,
THEREFORE, THAT THE VITAMIN D RECEPTOR SHARES
AN EVOLUTIONARY RELATIONSHIP WITH RECEPTORS
FOR STEROID HORMONES, THYROID HORMONE,
RETINOIDS, AND MANY ORPHAN RECEPTORS (WITH
NO KNOWN LIGAND).
Bind with intrcellular receptors – Gene expression in
target cells
VITAMIN D REPCEPTOR:
TRANSCRIPTIONAL REGULATION

THE SUPERGENE FAMILY OF NUCLEAR
RECEPTORS THAT INCLUDES THE VITAMIN D
RECEPTOR ALSO INCLUDES RECEPTORS FOR
CORTISOL, ESTROGEN, TESTOSTERONE,
THYROID HORMONE, ALDOSTERONE,
RETINOIC ACID, AND OTHERS. MANY
RECEPTORS IN THIS FAMILY HAVE NO KNOWN
LIGAND, AND MAY FUNCTION VIA
ALTERATIONS IN PHOSPHORYLATION STATE,
AND/OR ??.
VITAMIN D MECHANISM OF
ACTION
VIT D / VDR
RNA POL
5’ UNTRANSLATED REGION
VITAMIN D RESPONSIVE GENE
TRANSCRIPTION START SITE
IN THE NUCLEUS
ACTIONS OF 1,25 DHCC



GUT
 To help calcium absorption. STIMULATE TRANSEPITHELIAL
TRANSPORT OF CALCIUM AND PHOSPHATE IN THE SMALL
INTESTINE (PRINCIPALLY DUODENUM). Induce synthesis of
calcium binding proteins,calbinding,&calcium dependantATPase.
BONE
 STIMULATE TERMINAL DIFFERENTIATION OF OSTEOCLASTS
 STIMULATE OSTEOBLASTS TO STIMULATE OSTEOCLASTS TO
MOBILIZE CALCIUM = BONE RESORPTION
KIDNEYS: INCREASE RENAL REABSORPTION OF
CALCIUM&PHOSPAHTES
PARATHYROID

INHIBIT TRANSCRIPTION OF THE PTH GENE (FEEDBACK REGULATION)
Calcitonin


Produced by Parafollicular C cells of Thyroid in
response to increased iCa++
Actions





Inhibit osteoclastic resorption of bone
Increase renal Ca++ and PO43- excretion
Non-essential hormone. Patients with total
thyroidectomy maintain normal Ca++
concentrations
Useful in monitoring treatment of Medullary
Thyroid cancer
Used in treatment of Pagets’, Osteoporosis
ORGAN PHYSIOLOGY AND
CALCIUM METABOLISM

THERE ARE THREE PRICIPLE TISSUES THAT
FUNCTION PROMINENTLY IN CALCIUM
HOMEOSTATIS. DISORDERS OF THESE
TISSUES, OR OF THE CALCIOTROPIC FACTORS
THAT AFFECT THEIR FUNCTION MAY RESULT
IN DISORDERS OF CALCIUM METABOLISM



INTESTINES
KIDNEYS
BONE
ORGAN PHYSIOLOGY AND
CALCIUM METABOLISM

IT HELPS TO THINK IN TERMS OF THE “IN” AND “OUT” FACTORS
WE DISCUSSED AT THE BEGINNING OF THIS SECTION.
THEREFORE, THE ORGAN INFLUENCES OF INTESTINAL
ABSORPTION, BONE RESORPTION AND FORMATION, AND RENAL
EXCRETION CONTRIBUTE TO MAINTAINANCE OF NORMAL BLOOD
CALCIUM. INCORPORATE YOUR UNDERSTANDING OF THE ABOVE
HORMONES, AND NORMAL CALCIUM METABOLISM ASSUMES THE
LOGIC CHARACTERISIC OF THE STUDY OF ENDOCRINOLOGY.
DISORDERS IN ORGAN PHYSIOLOGY AND/OR HORMONE
FUNCTION MAY RESULT IN DISEASE.
GI PHYSIOLOGY

NORMAL INTESTINAL FUNCTION AND NORMAL
RESPONSE TO VITAMIN D ARE REQUIRED FOR NORMAL
CALCIUM ABSORPTION.
 GI DYSFUNCTION: SHORT BOWEL, MALABSORPTION
SYNDROMES, INFLAMMATORY BOWEL SYNDROMES
 AVAILABILITY AND FUNCTION OF VITAMIN D
(DIETARY AND/OR ENDOGENOUS)
 DIETARY CALCIUM INTAKE
 DIETARY PHOSPHATE INHIBITS Ca ABSORPTION
RENAL PHYSIOLOGY

RENAL FUNCTION



RESPONSE TO PTH
 1,25(OH)2D PRODUCTION
 TUBULAR RESPONSE (Ca REABSORPTION)
NORMAL FUNCTION IN 1,25(OH)2D SYNTHESIS
 1,25(OH)2D SUPPLEMENTATION IN RENAL
INSUFFICIENCY/FAILURE
NORMAL TUBULAR PHYSIOLOGY
 GENETIC RENAL CALCIUM LEAK
 HYPERCALCIURIA, WITH SECONDARY
HYPERPARATHYROIDISM
BONE PHYSIOLOGY

BONE IS A RESERVOIR OF CALCIUM, CALCIUM
EN MASSE BEING REQUIRED TO MAKE AND
MAINTAIN THE SKELETON. TO BE AN
EFFECTIVE RESERVOIR FOR THE
MAINTAINANCE OF NORMAL BLOOD CALCIUM,
CALCIUM MUST BE ABLE TO BE INCORPORATED
INTO, AND LIBERATED FROM, BONE ON SHORT
NOTICE.
BONE PHYSIOLOGY, cont.

BONE TURNOVER: A COUPLED PROCESS OF
BONE FORMATION AND BONE RESORPTION
(BREAK DOWN)
 TAKES PLACE THROUGHOUT LIFE
 SHIFT TOWARD FORMATION OR
RESORPTION REMOVES Ca FROM BLOOD OR
PUTS Ca INTO BLOOD, RESPECTIVELY, AND
CORRESPOND-INGLY AFFECTS BONE MASS.
BONE PHYSIOLOGY, cont.:
BONE TURNOVER

SKELETAL MASS IN THE HUMAN REACHES A
PEAK AT ABOUT AGE 30



PRIOR TO THAT, AS SKELETAL MASS IS
INCREASING, BONE FORMATION EXCEEDS BONE
RESORPTION.
AT PEAK BONE MASS, THE TWO PROCESSES ARE
EXACTLY MATCHED
AFTER THE AGE OF PEAK BONE MASS, SKELETAL
MASS IS LOST FOR THE REST OF LIFE
BONE PHYSIOLOGY, cont.

BONE FORMATION IS MEDIATED BY
OSTEOBLASTS

BONE RESORPTION IS MEDIATED BY
OSTEOCLASTS

PNEMONIC: OSTEOBLASTS BUILD;
OSTEOCLASTS, WELL, THEY DON’T
MEASUREMENT OF BONE
TURNOVER

THE COUPLED PROCESS OF BONE TURNOVER
CAN BE MEASURED BY:

MARKERS OF OSTEOBLAST METABOLISM



SERUM BONE-SPECIFIC ALKALINE PHOSPHATASE
SERUM OSTEOCALCIN
MARKERS OF OSTEOCLAST METABOLISM

URINE PRODUCTS OF BONE COLLAGEN BREAKDOWN



HYDROXYPROLINE
N-TELOPEPTIDES
PYRIDINIUM CROSSLINKS
BONE PHYSIOLOGY, cont.

HORMONAL CHAIN OF COMMAND:


NOTE THAT OSTEOCLASTS RESORB BONE, AND THAT
1,25(OH)2D AND PTH STIMULATE BONE RESORPTION.
HOWEVER, OSTEOCLASTS HAVE RECEPTORS FOR NEITHER
PTH NOR 1,25(OH)2D

PTH AND 1,25(OH)2D RECEPTORS ARE EXPRESSED ON
OSTEOBLASTS. THE OSTEOBLASTS, IN RESPONSE TO THESE
HORMONES, SEND A PARACRINE SIGNAL TO OSTEOCLASTS TO
TERMINALLY DIFFERENTIATE (VIT. D INFLUENCE) AND
RESORB BONE (PTH INFLUENCE).
BONE PHYSIOLOGY, cont.

WHEN THE COUPLED PROCESS OF BONE TURNOVER
(FORMATION AND RESORPTION) IS SHIFTED IN FAVOR
OF RESORPTION, THERE IS RELATIVE OR NET BONE
LOSS. THIS OCCURS IN A VARIETY OF CONDITIONS:






age
menopause in women or hypogonadism in men
glucocorticoid therapy
hyperparathyroidism (primary of secondary)
defects in organ physiology (GI, RENAL, BONE)
others (medications, genes, comorbid conditions, etc.)
BONE PHYSIOLOGY, cont.

IN A BROAD SENSE, FRACTURE RISK IS INVERSELY
PROPORTIONAL TO BONE MASS
 accelerated bone loss increases fracture risk




menopause
chronic and/or high dose glucocorticoid therapy
others
failure to reach normal peak bone mass means lower
bone mass per age later in life, and therefore
increases fracture risk

soda pop doesn’t provide calcium or vitamin D!!
BONE MASS AS A FUNCTION
OF AGE; PERTURBATIONS
PEAK BONE MASS
NORMAL
FAILURE TO REACH PEAK
ACCELERATED LOSS
BONE
MASS
THEORETICAL
FRACTURE
THRESHOLD
AGE
APPLIED ASPECTS





Hypoparathyroidism&
Hypocalcemia,Tetany.
Rickets
Osteomalacia
Osteoporosis
Hyperparathyroidism.
Hypocalcemia

Decreased PTH




Resistance to PTH



Genetic disorders
Bisphosphonates
Vitamin D abnormalities



Surgery
Hypomagnesemia
Idiopathic
Vitamin D deficiency
Rickets (VDR or Renal hyroxylase abnormalities)
Binding of Calcium


Hyperphosphate states (Crush injury, Tumor lysis, etc.)
Blood Transfusion (Citrate)
Hypoparathyroidism



Truehypoparathyroidism:1. Post operative
during thyroidectomy
2. Idiopathic.
Here Decreased secretion of PTH.
Pseudohypoparathyroidism: PTH secretion
is normal but non responsiveness of PTH
receptors of target tissues.
Hypoparathyroidism leads to
Hypocalcemia
Hypocalcemia





Causes: Hypoparathyroidism , Alkalosis.
Decreased plasma calcium <4-8mg% and
ionised calcium<3mg%. This leads to clinical
condition = TETANY
TETANY:
1. Latent tetany: (Sub clinical) –Assessed by –
Trausseau’s sign & Chvostek’s sign.
2. Manifest Tetany:Carpal &
pedal(rare)spasm,Laryngeal stridorasphyxia,Visceral features-bronchospasm,etc
HYPOCALCEMIA: SIGNS AND
SYMPTOMS

NEUROMUSCULAR:

CNS: IRRITABILITY, SEIZURES, PERSONALITY CHANGE,
INVOLUNTARY MUSCLE CONTRACTION
(TETANY), 7TH CRANIAL NERVE EXCITABILITY (CHVOSTEK’S SIGN),
NUMBNESS AND TINGLING IN FACE, HANDS, AND FEET,
TROUSSEAU’S SIGN
IMPAIRED COGNITION

CARDIOVASCULAR: QT PROLONGATION ON ECG, IN THE
EXTREME, ELECTROMECHANICAL DISSOCIATION MAY OCCUR
HYPOCALCEMIA: SIGNS AND
SYMPTOMS

AS WAS NOTED ABOVE FOR
HYPERCALCEMIA, THERE IS NO FIXED
LEVEL OF BLOOD CALCIUM AT WHICH
SIGNS AND/OR SYMPTOMS DEVELOP.
THIS VARIES FROM PATIENT TO
PATIENT, AND MAY BE INFLUENCED BY
COMORBID CONDITIONS.
CAUSES OF HYPOCALCEMIA

HYPOPARATHYROIDISM





HYPOVITAMINOSIS D




POSTSURGICAL (MOST COMMON)
AUTOIMMUNE
PSEUDOHYPOPARATHYROIDISM (PTH RESISTANCE)
IDIOPATHIC
DIETARY DEFICIENCY
RICKETS, OSTEOMALACIA
ORGAN DYSFUNCTION
 GI MALABSORPTION, RENAL LOSS
ENDOCRINE RESPONSE TO NON-HYPOPARATHYROID
HYPOCALCEMIA

SECONDARY HYPERPARATHYROIDISM (2o HPT)
HYPOCALCEMIA:
HYPOPARATHYROIDISM

POSTSURGICAL


MOST COMMON CAUSE OF HYPOPARATHYROIDISM
AUTOIMMUNE

MAY CLUSTER WITH OTHER AUTOIMMUNE ENDOCRINE
DISEASES, INCLUDING IDDM, AUTOIMMUNE THYROID
DISEASE, ADDISON’S, ETC. THIS IS RATHER UNCOMMON.
HYPOPARATHYROIDISM:
TREATMENT





GOAL: MAINTAIN ADEQUATE BLOOD CALCIUM
WITHOUT CAUSING SIDE EFFECTS
PTH IS NOT AVAILABLE CLINICALLY FOR REPLACEMENT
THERAPY
TREATMENT CENTERS ON THE USE OF VITAMIN D AND
CALCIUM SUPPLEMENTATION
VITAMIN D AND CALCIUM CAN MAINTAIN BLOOD
CALCIUM VIA ENHANCED GI ABSORPTION
ABSENCE OF PTH ALLOWS UNRESTRICTED URINARY
LOSS
HYPOPARATHYROIDISM:
TREATMENT SUMMARY
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VITAMIN D AND CALCIUM SUPPLEMENTS
TO MAINTAIN BLOOD CALCIUM AT LOW
END OF NORMAL
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PREVENT SYMPTOMS OF HYPOCALCEMIA
MINIMIZE URINARY CALCIUM LOSSES
USUALLY USE PRESCRIPTION STRENGTH
VITAMIN D
HYPOCALCEMIA:
HYPOVITAMINOSIS D
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THIS CATEGORY INCLUDES A NUMBER
OF CONDITIONS RELATED TO VITAMIN D
AVAILABILITY, METABOLISM, OR
FUNCTION
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INADEQUATE DIETARY SUPPLY
INADEQUATE EXPOSURE TO SUNLIGHT
DEFECTS IN VITAMIN D SYNTHESIS
DEFECTS IN VITAMIN D RECEPTOR
DEFECTIVE VITAMIN D
FUNCTION
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CLINICAL SYNDROMES BROADLY
CATEGORIZED AS RICKETS AND
OSTEOMALACIA.
DIMINISHED GI ABSORPTION OF Ca
TENDENCY TOWARD HYPOCALCEMIA
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SECONDARY HYPERPARATHYROIDISM
NON-PARATHYROID HYPOCALCEMIA:
SECONDARY HYPERPARATHYROIDISM
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IN HYPOVITAMINOSIS D (RICKETS AND
OSTEOMALACIA), LOW LEVELS OF, OR DEFECTIVE
FUNCTION OF, VITAMIN D CAUSE TENDENCY TOWARD
HYPOCALCEMIA. THE PARATHYROIDS RESPOND
APPROPRIATELY BY INCREASING PTH SECRETION TO
MAINTAIN NORMAL BLOOD CALCIUM.
THIS IS REFERRED TO AS SECONDARY
HYPERPARATHYROIDISM: ELEVATED PTH IN RESPONSE
TO (SECONDARY TO) SOME NON-PARATHYROID
PROBLEM
RICKETS
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In children.
Mineralization of organic bone bone matrix is
defective.
Causes & types:
1. Vit.D deficiency rickets-a. Nutritionalb.
Deficient synthesis due to lack of exposure to
sun light(uv rays).
2. VitD resistant rickets: non forming of
1,25DHCC OR no response to it( receptor level)
Features of Rickets
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Bony defects:Craniotabes(areas in membranous
skull yeilding to pressure), Widening of wrists,
Chest deformities, Rickety rosary( beading of
costochondral junctions), Bowing of legs/knock
knee, Kyphosis.
General: delayed mile stones.
Biochemical:Decreased plasma cal, CaXPO4<60(
normal 60),decreased 1,25DHCC
Tetany : if sever hypocalcemia
Rickets
RICKETS AND
OSTEOMALACIA(malacia=softening)
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DISEASES OF DEFECTIVE BONE MINERALIZATION
THESE DISEASES ARE PATHOPHYSIOLOGICALLY RELATED, AND
DIFFER MAINLY IN THE AGE AT WHICH THEY BECOME MANIFEST
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RICKETS IS A DISEASE OF CHILDHOOD
OSTEOMALACIA IS A DISEASE OF ADULTHOOD
WIDE RANGING CATEGORY OF DISEASE
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DISORDERS OF VITAMIN D
PHOSPHATE DEFICIENCY
CHRONIC RENAL FAILURE (ALSO RENAL OSTEODYSTROPHY)
PRIMARY DISORDERS OF BONE METABOLISM
RICKETS AND OSTEOMALACIA:
CLINICAL MANIFESTATIONS
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RICKETS MAY RESULT IN CHARACTERISTIC BONY
DEFORMITIES IN CHILDREN
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RICKETS USUALLY IS ASSOCIATED WITH SHORT
STATURE
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OSTEOMALACIA IN ADULTS GENERALLY DOES NOT CAUSE
BONY DEFORMITIES
OSTEOMALACIA (ONSET IN ADULTHOOD) DOES NOT CAUSE
SHORT STATURE
PATIENTS MAY SUFFER BONE PAIN (NOT SEEN IN
OSTEOPOROSIS UNLESS THERE IS A FRACTURE)
FRACTURE RISK IS INCREASED
RICKETS AND
OSTEOMALACIA: CAUSES
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NUTRITIONAL DEFICIENCY OF VITAMIN D AND/OR INADEQUATE
SUNLIGHT EXPOSURE:
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EASILY TREATED WITH DIETARY SUPPLEMENTATION
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FORTIFIED MILK - PROVIDES VITAMIN D AND CALCIUM
MULTIPLE VITAMIN - PROVIDES VITAMIN D ONLY
EITHER WAY, MUST ASSURE ADEQUATE CALCIUM WITH THE VITAMIN D
DEFECTIVE RENAL 1a-HYDROXYLATION OF 25(OH) VIT. D
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AUTOSOMAL RECESSIVE
CHARACTERIZED BY HYPOCALCEMIA, HYPOPHOSPHATEMIA,
SECONDARY HYPERPARATHYROIDISM, LOW 1,25(OH)2D, AND
INCREASED ALKALINE PHOSPHATASE
TREATMENT IS BY GIVING 1,25(OH)2D AND CALCIUM
RICKETS AND OSTEOMALACIA:
CAUSES, cont.
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TISSUE RESISTANCE TO 1,25(OH)2D
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AUTOSOMAL RECESSIVE, OR ACQUIRED
DEFECT IN NUCLEAR RECEPTOR FOR VITAMIN D
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DEFECTIVE SYNTHESIS OF RECEPTOR
DEFECTIVE AFFINITY OF RECEPTOR FOR 1,25(OH)2D
DEFECTIVE ABILITY OF 1,25(OH)2D/VITAMIN D RECEPTOR
COMPLEX TO INTERACT WITH DNA OR ACTIVATE
TRANSCRIPTIONAL MACHINERY PROPERLY
TREATMENT IS WITH 1,25(OH)2D AND CALCIUM
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RESPONSE TO THERAPY IS VARIABLE GIVEN DIVERSITY OF
MOLECULAR DEFECTS (ABOVE)
RICKETS AND OSTEOMALACIA:
CAUSES, cont.
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ANITCONVULSANT-INDUCED OSTEOMALACIA:
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PATIENTS TREATED CHRONICALLY WITH
DIPHENYLHYDANTOIN (PHENYTOIN, DILANTIN©) OR
PHENOBARBITAL FOR SEIZURE DISORDERS ARE AT RISK FOR
ANTICONVULSANT-INDUCED OSTEOMALACIA
THESE DRUGS ALTER AND ACCELERATE HEPATIC METABOLISM
OF VITAMIN D, AND THIS IS THOUGHT TO PLAY A MAJOR
ROLE IN THIS DISORDER
ASSURANCE OF ADEQUATE VITAMIN D INTAKE IS
ENCOURAGED IN THESE PATIENTS
NEWER ANTICONVULSANTS, SUCH AS VALPROIC ACID,
CARBAMAZEPINE, GABAPENTIN, ETC. HAVE NOT BEEN
IMPLICATED AS OF YET
Osteoporosis
Primary = Senile osteoporosis and more
commonly post menopausal.
 Secondary: due to excess of
glucocorticoids, hyperparathyroidism etc.
Mainly loss of bone matrix i.e loss of collgin
fibers with some loss of calcium salt.
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Osteoporosis
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Symptoms of Osteoporosis
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There are no symptoms in the early stages of
the disease.
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Symptoms occurring late in the disease include:
Joint pain and tenderness
Swelling
Warmth over the affected joint
HYPERCALCEMIA
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HYPERCALCEMIA IS THE STATE OF BLOOD
CALCIUM CONCENTRATION ABOVE THE
NORMAL RANGE
RELATE TO ORGAN PHYSIOLOGY AND
ENDOCRINE PHYSIOLOGY DISCUSSED ABOVE:
“IN” AND “OUT” FACTORS
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GI, RENAL, BONE
PTH, VITAMIN D
TO MUCH CALCIUM ENTERING BLOOD AND/OR TOO LITTLE
LEAVING BLOOD
Hypercalcemia
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Hyperparathyroidism
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Malignancy
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Overproduction of 1,25 (OH)2D
Drug-Induced
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Humoral Hypercalcemia
PTHrP (Lung Cancer)
Osteoclastic activity (Myeloma, Lymphoma)
Granulomatous Diseases
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Primary, Secondary, Tertiary
MEN Syndromes
Thiazides
Lithium
Milk-Alkali
Vitamin A, D
Renal failure
Hypercalcemia
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Signs & Symptoms
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Medical Treatment
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Bones (Osteitis fibrosa cystica, osteoporosis, rickets)
Stones (Renal stones)
Groans (Constipation, peptic ulcer)
Moans (Lethargy, depression, confusion)
SERM’s (Evista)
Bisphosphonates (Pamidronate)
Calcitonin (for severe cases)
Saline diuresis
Glucocorticoids (for malignant/granulomatous diseases)
Avoid thiazide diuretics
Surgical Treatment
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Single vs. Double adenoma – simple excision
Multiple Gland hyperplasia – total parathyroid with autotransplant vs.
3½ gland excision
Primary Hyperparathyroidism
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Diagnosis
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Signs & Symptoms
Elevated serum calcium
Elevated PTH
Etiology
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Solitary Adenoma (80-85%)
Double Adenomas (2-4%)
Muliple Gland Hyperplasia (10-30%)
Parathyroid Carcinoma (0.5%)
MEN syndromes (10% of MGH have MEN 1)
Multiple Endocrine Neoplasia
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MEN 1
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MEN 2a
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Pituitary adenoma
Pancreatic endocrine tumor
Parathyroid neoplasia (90%)
Medullary thyroid cancer (100%)
Pheochromocytoma (50%)
Parathyroid neoplasia (10-40%)
MEN 2b
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Medullary thyroid cancer (100%)
Pheochromocytoma (50%)
Neuromas (100%)
Parathyroidectomy
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1990 NIH Guidelines
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Serum Ca++ > 12 mg/dl
Hypercalciuria > 400 mg/day
Classic symptoms
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Nephrolithiasis
Osteitis fibrosa cystica
Neuromuscular disease
Cortical bone loss with DEXA Z score < -2
Reduced creatinine clearance
Age < 50
Other considerations
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Vertebral osteopenia
Vitamin D deficency
Perimenopause
Preoperative Localization
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Thallium / Pertechnetate
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Technetium 99m Sestamibi
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Based on subtraction of Tc 99 which concentrates only in thyroid
from background Thallium which is absorbed by thyroid and
parathyroid
Moderate sensitivity and specificity
Thyroid pathology reduces effectiveness
Absorbed by thyroid and abnormal parathyroid
Early washout from thyroid leaves residual parathyroid signals in
later images
Higher sensitivity and specificity
Single Photon Emission Computed Tomography
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Creates a three dimensional representation to allow for ectopic
localization
Not commonly used
HYPERCALCEMIA: SIGNS
AND SYMPTOMS
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SIGNS AND SYMPTOMS DEPEND ON THE
DEGREE OF HYPERCALCEMIA AND COMORBID
CONDITIONS
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THERE IS NO ABSOLUTE VALUE OF BLOOD CALCIUM
AT WHICH SYMPTOMS DEVELOP. LEVEL OF BLOOD
CALCIUM AT WHICH SYMPTOMS DEVELOP VARY
FROM PATIENT TO PATIENT.
HYPERCALCEMIA: SIGNS
AND SYMPTOMS
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CNS: altered MS, including lethargy, depression,
decreased alertness, confusion, obtundation, and coma
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GI: anorexia, constipation, nausea, and vomiting
RENAL: diuresis, impaired concentrating ability,
dehydration. Hypercalciuria is a risk for kidney stones.
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SKELETAL: most causes of hypercalcemia are
associated with increased bone resorption, and thus,
fracture risk
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CARDIOVASCULAR: cause/exacerbate HTN,
shortened QT interval
CAUSES OF
HYPERCALCEMIA
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HORMONAL
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NON-HORMONAL
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PRIMARY HYPERPARATHYROIDISM
HYPERVITAMINOSIS D
PARANEOPLASTIC (e.g., PTHrP, cytokines)
RENAL FAILURE
MILK-ALKALI SYNDROME
DRUGS
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THIAZIDES, LITHIUM, OTHERS
PRIMARY
HYPERPARATHYROIDISM
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PRIMARY HYPERPARATHYROIDISM (1o HPT) is
the most common cause of hypercalcemia in the
healthy outpatient setting
RESULTS FROM AN ADENOMA, MULTIPLE
ADENOMAS, OR HYPERPLASIA OF THE
PARATHYROIDS. MALIGNANCY IS
FORTUNATELY VERY RARE. THE DEFECT LIES
WITH THE PARATHYROID TISSUE.
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COMPARE SECONDARY HYPERPARA-THYROIDISM (2o
HPT), BELOW
PRIMARY
HYPERPARATHYROIDISM
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1o HPT is characterized by
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hypercalcemia
PTH above the normal range
hypercalciuria
increased risk of fractures
increased risk of kidney stones
seldom causes extreme hypercalcemia unless
confounded by renal failure, dehydration, etc.
QESTIONS
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
How much calcium we have in our body?
Name the dietary sources of calcium.
What is daily dietary requirements?
In which forms calcium is present in our body?
Mention the functions of calcium.
Name 3 organs related to cal.metabolism
Name 3 hormones related to it.
Name other hormones influencing metabolism
Site of synthesis& mechanism of action of PTH
Actions of PTH
QESTIONS
11. Describe formation of 1,25DHCC
12. Which factors regulate synthesis of it.
13. Mechanism of action of 1,25DHCC
14. Actions of 1,25DHCC.
15. Describe the hormonal regulation of blood
calcium.
16. Describe TETANY.
17. Describe RICKTES.
18. Describe OSTEOMALACIA.
19. Describe OSTEOPOROSIS.