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CALCIUM METABOLISM CALCIUM METABOLISM PHYSIOLOGY OF CALCIUM ... Presentation Transcript

  • 1. CALCIUM METABOLISM
  • 2. CALCIUM METABOLISM
    • PHYSIOLOGY OF CALCIUM METABOLISM
      • ORGAN SYSTEMS INVOLVED
      • HORMONES INVOLVED
    • HYPERCALCEMIA
    • HYPOCALCEMIA
    • METABOLIC BONE DISEASES
  • 3. CALCIUM PHYSIOLOGY: BLOOD CALCIUM
    • BLOOD CALCIUM IS TIGHTLY REGULATED
      • PRINCIPLE ORGAN SYSTEMS
        • GUT, BONE, KIDNEYS
      • HORMONES
        • PARATHYROID HORMONE (PTH), VITAMIN D
      • INTEGRATED PHYSIOLOGY OF ORGAN SYSTEMS AND HORMONES MAINTAIN BLOOD CALCIUM
  • 4. CALCIUM PHYSIOLOGY: BLOOD CALCIUM
    • CALCIUM FLUX INTO AND OUT OF BLOOD
      • “ IN” FACTORS: INTESTINAL ABSORPTION, BONE RESORPTION
      • “ OUT” FACTORS: RENAL EXCRETION, BONE FORMATION (Ca INCORPATION INTO BONE)
      • BALANCE BETWEEN “IN” AND “OUT” FACTORS
        • ORGAN PHYSIOLOGY OF GUT, BONE, AND KIDNEY
        • HORMONE FUNCTION OF PTH AND VITMAMIN D
  • 5. CALCIUM HOMEOSTASIS DIETARY CALCIUM INTESTINAL ABSORPTION ORGAN PHYSIOLOGY ENDOCRINE PHYSIOLOGY DIETARY HABITS, SUPPLEMENTS BLOOD CALCIUM BONE KIDNEYS URINE THE ONLY “IN” THE PRINCIPLE “OUT” ORGAN PHYS. ENDOCRINE PHYS. ORGAN, ENDOCRINE
  • 6. 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.
  • 7. 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 D 3
        • ROLE OF SUNLIGHT IN VITAMIN D ADEQUACY
  • 8. VITAMIN D SYNTHESIS
    • VITAMIN D 3 CIRCULATES TO THE LIVER ,
    • WHERE THE ENZYME 25-HYDROXYLASE HYDROXYLATES IT TO 25-HYDROXY 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
  • 9. VITAMIN D SYNSTHESIS
    • 25(OH)VITAMIN D CIRCULATES TO THE KIDNEYS , WHERE THE ENZYME RENAL 1  -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 1  -HYDROXYLASE IS REGULATED BY PTH WHICH STIMULATES ITS ACTIVITY. PTH IS THE PRINCIPLE PHYSIOLOGIC REGULATOR, ALTHOUGH CALCIUM CAN AFFECT THE ACTIVITY.
  • 10. VITAMIN D SYNTHESIS SKIN LIVER KIDNEY 7- DEHYDROCHOLESTEROL VITAMIN D 3 VITAMIN D 3 25(OH)VITAMIN D h  25-HYDROXYLASE 25(OH)VITAMIN D 1,25(OH) 2 VITAMIN D ( ACTIVE METABOLITE ) 1  -HYDROXYLASE TISSUE-SPECIFIC VITAMIN D RESPONSES
  • 11. 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.
  • 12. 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).
  • 13. VITAMIN D REPCEPTOR: TRANSCRIPTIONAL REGULATION
    • THE SUPERGENE FAMILY OF NUCLEAR RECEPTORS 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 other factors.
  • 14. VITAMIN D MECHANISM OF ACTION 5’ UNTRANSLATED REGION VITAMIN D RESPONSIVE GENE TRANSCRIPTION START SITE RNA POL VIT D / VDR IN THE NUCLEUS
  • 15. FUNCTION OF VITAMIN D
    • TISSUE SPECIFICITY
      • GUT
        • STIMULATE TRANSEPITHELIAL TRANSPORT OF CALCIUM AND PHOSPHATE IN THE SMALL INTESTINE (PRINCIPALLY DUODENUM)
      • BONE
        • STIMULATE TERMINAL DIFFERENTIATION OF OSTEOCLASTS
        • STIMULATE OSTEOBLASTS TO STIMULATE OSTEOCLASTS TO MOBILIZE CALCIUM
      • PARATHYROID
        • INHIBIT TRANSCRIPTION OF THE PTH GENE (FEEDBACK REGULATION)
  • 16. 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
  • 17. 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.
  • 18. CALCIUM, PTH, AND VITAMIN D FEEDBACK LOOPS NORMAL BLOOD Ca RISING BLOOD Ca FALLING BLOOD Ca SUPPRESS PTH STIMULATE PTH BONE RESORPTION URINARY LOSS 1,25(OH) 2 D PRODUCTION BONE RESORPTION URINARY LOSS 1,25(OH) 2 D PRODUCTION
  • 19. CALCIUM FEEDBACK TO REGULATE PTH SECRETION
    • CALCIUM-SENSING RECEPTOR IN THE PARATHYROIDS
      • 7TMD receptor THAT BINDS Ca 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
  • 20. 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.
  • 21. 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 (G s ). BINDING PTH TO THE RECEPTOR CAUSES GDP TO DISSOCIATE FROM G s 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.
  • 22. 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 G s , 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.
  • 23. ORGAN PHYSIOLOGY AND CALCIUM METABOLISM
    • THERE ARE 3 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
  • 24. ORGAN PHYSIOLOGY AND CALCIUM METABOLISM
    • IT HELPS TO THINK IN TERMS OF THE “IN” AND “OUT” FACTORS WE have DISCUSSED
    • 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
    • DISORDERS IN ORGAN PHYSIOLOGY AND/OR HORMONE FUNCTION MAY RESULT IN DISEASE.
  • 25. 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
  • 26. RENAL PHYSIOLOGY
    • RENAL FUNCTION
      • RESPONSE TO PTH
        • 1,25(OH) 2 D PRODUCTION
        • TUBULAR RESPONSE (Ca REABSORPTION)
      • NORMAL FUNCTION IN 1,25(OH) 2 D SYNTHESIS
        • 1,25(OH) 2 D SUPPLEMENTATION IN RENAL INSUFFICIENCY/FAILURE
      • NORMAL TUBULAR PHYSIOLOGY
        • GENETIC RENAL CALCIUM LEAK
          • HYPERCALCIURIA, WITH SECONDARY HYPERPARATHYROIDISM
  • 27. 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.
  • 28. 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.
  • 29. 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
  • 30. BONE PHYSIOLOGY, cont.
    • BONE FORMATION IS MEDIATED BY OSTEOBLASTS
    • BONE RESORPTION IS MEDIATED BY OSTEOCLASTS
    • PNEMONIC: OSTEO B LASTS B UILD; OSTEO C LASTS, WELL, THEY DON’T
  • 31. 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
  • 32. 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.)
  • 33. CIRCULATING CALCIUM,
    • IONIZED CALCIUM (FREE CALCIUM)
      • RESPONSIBLE FOR CALCIUM FUNCTION
      • CAN BE DIRECTLY MEASURED
  • 34. HYPERCALCEMIA: SIGNS AND SYMPTOMS
    • SIGNS AND SYMPTOMS DEPEND ON THE DEGREE OF HYPERCALCEMIA AND COMORBID CONDITIONS
      • 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.
  • 35. HYPERCALCEMIA: SIGNS AND SYMPTOMS
    • CNS : altered behavior, including lethargy, depression, decreased alertness, confusion, obtundation, and coma
    • GI : anorexia, constipation, nausea, and vomiting
    • RENAL : diuresis, impaired concentrating ability, dehydration. Hypercalciuria is a risk for kidney stones.
    • SKELETAL : most causes of hypercalcemia are associated with increased bone resorption, and thus, fracture risk
    • CARDIOVASCULAR : cause/exacerbate HTN
  • 36. CAUSES OF HYPERCALCEMIA
    • HORMONAL
      • PRIMARY HYPERPARATHYROIDISM
      • HYPERVITAMINOSIS D
      • PARANEOPLASTIC (e.g., PTHrP, cytokines)
    • NON-HORMONAL
      • RENAL FAILURE
      • MILK-ALKALI SYNDROME
    • DRUGS
      • THIAZIDES, LITHIUM, OTHERS
  • 37. PRIMARY HYPERPARATHYROIDISM
    • PRIMARY HYPERPARATHYROIDISM (1 o 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.
      • COMPARE SECONDARY HYPERPARA-THYROIDISM (2 o HPT), BELOW
  • 38. PRIMARY HYPERPARATHYROIDISM
    • 1 o HPT is characterized by
      • 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.
  • 39. PRIMARY HYPERPARATHYROIDISM
    • CAUSES OF 1 o HPT
      • SPORADIC ADENOMA(S) MOST COMMON CAUSE
      • MULTIPLE ENDOCRINE NEOPLASIA TYPE 1 (MEN-1): PARATHYROID TUMORS (AND PITUITARY AND PANCREAS). LOSS OF ACTIVITY OF TUMOR SUPPRESSOR GENE (the MENIN gene) FOUND ON HUMAN CHROMOSOME 11. THIS IS RARE.
      • MEN-2a: PARATHYROID TUMORS, MEDULLARY THYROID CANCER (OR HYPERPLASIA), AND PHEOCHROMOCYTOMA. ACTIVATING MUTATION OF ret PROTO-ONCOGENE ON HUMAN CHROMOSOME 10. THIS IS RARE.
  • 40. PRIMARY HYPERPARATHYROIDISM
    • CAUSES OF 1 o HPT, cont.
      • FAMILIAL HYPERPARATHYROIDISM: 1 o HPT WITHOUT THE OTHER TUMORS SEEN IN MEN-1 OR MEN-2a. THE GENE IS NOT KNOWN, BUT MAPS TO A REGION ON HUMAN CHROMOSOME 1.
      • FAMILIAL BENIGN HYPOCALCIURIC HYPERCALCEMIA: AN INACTIVATING MUTATION IN THE CALCIUM SENSING RECEPTOR FOUND IN THE PARATHYROIDS AND KIDNEYS, AND RESULTS IN HYPERCALCEMIA AND HYPERPARATHYROIDISM, BUT WITH LOW URINARY CALCIUM.
  • 41. TREATMENT OF PRIMARY HYPERPARATHYROIDISM
    • SURGICAL PARATHYROIDECTOMY IS CURATIVE
    • THERE ARE NO MEDICATIONS YET AVAILABLE TO TREAT THE DISEASE
    • SOME PATIENTS CAN BE WATCHED
      • NO CLINICAL CONSEQUENCES OF HYPERCALCEMIA (FRACTURE, STONES, ETC.)
      • MILD HYPERCALCEMIA
      • OLDER AGE GROUPS
    • AVOID DEHYDRATION
    • AVOID EXCESSIVE DIETARY CALCUIM
  • 42. HYPERVITAMINOSIS D
    • EXCESSIVE INTAKE OF VITAMIN D
      • RELATIVELY HARD TO DO IF ALL RELEVANT ORGAN SYSTEMS ARE FUNCTIONING PROPERLY; GENERALLY REQUIRES PRESCRIPTION STRENGTH VITAMIN D, PARTICULARLY 1,25(OH) 2 D (CALCITRIOL)
    • EXCESSIVE PRODUCTION OF 1,25(OH) 2 D
      • EXTRA-RENAL 1-HYDROXYLATION OF 25(OH)VITAMIN D BY AN ENZYME WITH 1-HYDROXYLASE ACTIVITY, BUT WHICH IS DISTINCT FROM THE RENAL ENZYME
        • USUALLY ASSOCIATED WITH GRANULOMAS (MACROPHAGES) OR ABNORMAL LYMPHOID TISSUE (B CELL LYMPHOMA)
        • NOT REGULATED BY PTH OR CALCIUM
  • 43. HYPERVITAMINOSIS D: CLINICAL CHARACTERISTICS
    • HYPERCALCEMIA
    • SUPPRESSED PTH
    • INCREASED 1,25(OH) 2 D
    • SOURCE
      • DIET?
      • GRANULOMA?
        • SARCOIDOSIS MOST COMMON; ALSO TB, OTHERS
      • LYMPHOMA?
  • 44. NON-HORMONAL HYPERCALCEMIA
    • MILK-ALKALI SYNDROME:
      • INTAKE OF HIGH DOSES OF CALCIUM AND ABSORBABLE ANTACID (SUCH AS NaCO 3 )
      • RARE CAUSE OF HYPERCALCEMIA NOW
        • MORE COMMONLY DESCRIBED IN EARLIER PART OF 20 TH CENTURY (NO H2 BLOCKERS OR PPI’S!!)
      • MECHANISM NOT ABSOLUTELY CLEAR:
        • INCREASED INTESTINAL ABSORPTION
        • DECREASED RENAL CLEARANCE
      • PTH SUPPRESSED, PTHrP NORMAL, 1,25(OH) 2 D NORMAL
  • 45. RENAL FAILURE-ASSOCIATED HYPERCALCEMIA
    • RENAL FAILURE MAY CAUSE EITHER HYPERCALCEMIA OR HYPOCALCEMIA
    • HYPERCALCEMIA USUALLY RESULTS FROM A COMBINATION OF FACTORS INCLUDING DECREASED CALCIUM CLEARANCE AND INCREASED BONE RESORPTION , +/- GI UPTAKE
      • PTH ELEVATION
      • LOW ENDOGENOUS 1,25(OH) 2 D
        • EXOGENOUS 1,25(OH) 2 D MAY CONTRIBUTE TO HYPERCALCEMIA
      • CALCIUM AND PHOSPHATE RENAL CLEARANCE IS ABOLISHED, AND DIALYSIS DOES A RELATIVELY POOR JOB AT CLEARANCE (COMPARED TO, SAY, POTASSIUM)
  • 46. DRUG-INDUCED HYPERCALCEMIA
    • THIAZIDE DIURETIC-INDUCED HYPERCALCEMIA :
      • STIMULATE RENAL TUBULAR CALCIUM REABSORPTION
        • DECREASE URINARY LOSS OF CALCIUM
      • UNCOMMON CAUSE OF HYPERCALCEMIA AT DOSES USED TO TREAT HYPERTENSION
        • MORE LIKELY IN COMBINATION WITH RENAL DISEASE, 1 o HPT, ETC.
  • 47. DRUG-INDUCED HYPERCALCEMIA, cont.
    • LITHIUM-INDUCED HYPERCALCEMIA :
      • LITHIUM MAY BE ASSOCIATED WITH HYPERCALCEMIA AT DOSES ROUTINELY USED TO TREAT BIPOLAR AFFECTIVE DISORDER (DURATION OF THERAPY IS A FACTOR)
      • SHIFTS “SET POINT” FOR CALCIUM REGULATION OF PTH SECRETION
        • PATHOPHYSIOLOGIC CORRELATE: CALCIUM-SENSING RECEPTOR, ABOVE
      • AUGMENTS PTH EFFECT AT TARGET TISSUES (BONE AND KIDNEY)
  • 48. DRUG-INDUCED HYPERCALCEMIA, cont.
    • HIGH DOSES OF VITAMIN A, OR RETINOIC ACID-INDUCED HYPERCALCEMIA :
      • VARIOUS RETINOIDS ARE USED IN TREATMENT OF ACNE, AND CERTAIN HEMATOLOGIC MALIGNANCIES
      • BIND TO RECEPTORS IN THE SUPERGENE FAMILY OF NUCLEAR RECEPTORS WHICH INCLUDES STEROID HORMONE, THYROID, VITAMIN D RECEPTORS, ETC.
      • APPEAR TO DIRECTLY ACTIVATE OSTEOCLASTS AND MEDIATE BONE RESORPTION
      • HYPERCALCEMIA IS ASSOCIATED WITH SUPPRESSED PTH, NORMAL PTHrP, NORMAL 1,25(OH) 2 D
  • 49. HYPOCALCEMIA
    • THE STATE OF BLOOD CALCIUM BELOW THE NORMAL RANGE
      • MOST ACCURATELY ASSESSED WITH IONIZED CALCIUM
      • TOTAL CALCIUM CANNOT BE ACCURATELY INTERPRETED WITHOUT KNOWING SERUM ALBUMIN
      • FAIRLY UNCOMMON
  • 50. 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.
  • 51. HYPOCALCEMIA: SIGNS AND SYMPTOMS
    • NEUROMUSCULAR : INVOLUNTARY MUSCLE CONTRACTION (TETANY), 7 TH CRANIAL NERVE EXCITABILITY (CHVOSTEK’S SIGN), NUMBNESS AND TINGLING IN FACE, HANDS, AND FEET, TROUSSEAU’S SIGN
    • CNS : IRRITABILITY, SEIZURES, PERSONALITY CHANGE, IMPAIRED COGNITION
    • CARDIOVASCULAR : QT PROLONGATION ON ECG, IN THE EXTREME, ELECTROMECHANICAL DISSOCIATION MAY OCCUR
  • 52. CAUSES OF HYPOCALCEMIA
    • HYPOPARATHYROIDISM
      • POSTSURGICAL (MOST COMMON)
      • AUTOIMMUNE
      • PSEUDOHYPOPARATHYROIDISM (PTH RESISTANCE)
      • IDIOPATHIC
    • HYPOVITAMINOSIS D
      • DIETARY DEFICIENCY
      • RICKETS, OSTEOMALACIA
    • ORGAN DYSFUNCTION
      • GI MALABSORPTION, RENAL LOSS
    • ENDOCRINE RESPONSE TO NON-HYPOPARATHYROID HYPOCALCEMIA
      • SECONDARY HYPERPARATHYROIDISM (2 o HPT)
  • 53. HYPOCALCEMIA: HYPOPARATHYROIDISM
    • POSTSURGICAL
      • MOST COMMON CAUSE OF HYPOPARATHYROIDISM
      • VITAL IMPORTANCE OF EXCELLENT ENT SURGEON EXPERIENCED IN THYROID AND PARATHYROID SURGERY
        • Dr. JEFFREY HALLER, MISSOULA, MONTANA, IS THE BEST
    • AUTOIMMUNE
      • MAY CLUSTER WITH OTHER AUTOIMMUNE ENDOCRINE DISEASES, INCLUDING IDDM, AUTOIMMUNE THYROID DISEASE, ADDISON’S, ETC. THIS IS RATHER UNCOMMON.
  • 54. 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
  • 55. HYPOPARATHYROIDISM: TREATMENT SUMMARY
    • VITAMIN D AND CALCIUM SUPPLEMENTS TO MAINTAIN BLOOD CALCIUM AT LOW END OF NORMAL
      • PREVENT SYMPTOMS OF HYPOCALCEMIA
      • MINIMIZE URINARY CALCIUM LOSSES
      • USUALLY USE PRESCRIPTION STRENGTH VITAMIN D
  • 56. HYPOCALCEMIA: HYPOVITAMINOSIS D
    • THIS CATEGORY INCLUDES A NUMBER OF CONDITIONS RELATED TO VITAMIN D AVAILABILITY, METABOLISM, OR FUNCTION
      • INADEQUATE DIETARY SUPPLY
      • INADEQUATE EXPOSURE TO SUNLIGHT
      • DEFECTS IN VITAMIN D SYNTHESIS
      • DEFECTS IN VITAMIN D RECEPTOR
  • 57. DEFECTIVE VITAMIN D FUNCTION
    • CLINICAL SYNDROMES BROADLY CATEGORIZED AS RICKETS AND OSTEOMALACIA .
    • DIMINISHED GI ABSORPTION OF Ca
    • TENDENCY TOWARD HYPOCALCEMIA
      • SECONDARY HYPERPARATHYROIDISM
  • 58. NON-PARATHYROID HYPOCALCEMIA: SECONDARY HYPERPARATHYROIDISM
    • 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
  • 59. HYPERPARATHYROIDISM: PRIMARY vs. SECONDARY
  • 60. SECONDARY HYPERPARATHYROIDISM
    • CAUSES: UNLIKE 1 o HPT, WHICH IS A PRIMARY DYSFUNCTION OF PARATHYROID TISSUE, 2 o HPT IS A NORMAL PHYSIOLOGIC RESPONSE OF THE PARATHYROIDS TO A THREAT OF HYPOCALCEMIA
    • THREE MAIN CATEGORIES OF NON-PARATHYROID DYSFUCTION
      • PROBLEMS WITH INTESTINAL ABSORPTION OF CALCIUM
      • INAPPROPRIATE URINARY LOSSES OF CALCIUM (RENAL LEAK)
      • DISORDERS OF VITAMIN D (DEFICIENCY, METABOLIC ERRORS, RESISTANCE, ETC.)
  • 61. RICKETS AND OSTEOMALACIA
    • DISEASES OF DEFECTIVE BONE MINERALIZATION
    • THESE DISEASES ARE PATHOPHYSIOLOGICALLY RELATED, AND DIFFER MAINLY IN THE AGE AT WHICH THEY BECOME MANIFEST
      • RICKETS IS A DISEASE OF CHILDHOOD
      • OSTEOMALACIA IS A DISEASE OF ADULTHOOD
    • WIDE RANGING CATEGORY OF DISEASE
      • DISORDERS OF VITAMIN D
      • PHOSPHATE DEFICIENCY
      • CHRONIC RENAL FAILURE (ALSO RENAL OSTEODYSTROPHY)
      • PRIMARY DISORDERS OF BONE METABOLISM
  • 62. RICKETS AND OSTEOMALACIA: CLINICAL MANIFESTATIONS
    • RICKETS MAY RESULT IN CHARACTERISTIC BONY DEFORMITIES IN CHILDREN
      • OSTEOMALACIA IN ADULTS GENERALLY DOES NOT CAUSE BONY DEFORMITIES
    • RICKETS USUALLY IS ASSOCIATED WITH SHORT STATURE
      • 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
  • 63. RICKETS AND OSTEOMALACIA: CAUSES
    • NUTRITIONAL DEFICIENCY OF VITAMIN D AND/OR INADEQUATE SUNLIGHT EXPOSURE:
      • EASILY TREATED WITH DIETARY SUPPLEMENTATION
        • 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 1  -HYDROXYLATION OF 25(OH) VIT. D
      • AUTOSOMAL RECESSIVE
      • CHARACTERIZED BY HYPOCALCEMIA, HYPOPHOSPHATEMIA, SECONDARY HYPERPARATHYROIDISM, LOW 1,25(OH) 2 D, AND INCREASED ALKALINE PHOSPHATASE
      • TREATMENT IS BY GIVING 1,25(OH) 2 D AND CALCIUM
  • 64. RICKETS AND OSTEOMALACIA: CAUSES, cont.
    • TISSUE RESISTANCE TO 1,25(OH) 2 D
      • AUTOSOMAL RECESSIVE, OR ACQUIRED
      • DEFECT IN NUCLEAR RECEPTOR FOR VITAMIN D
        • DEFECTIVE SYNTHESIS OF RECEPTOR
        • DEFECTIVE AFFINITY OF RECEPTOR FOR 1,25(OH) 2 D
        • DEFECTIVE ABILITY OF 1,25(OH) 2 D/VITAMIN D RECEPTOR COMPLEX TO INTERACT WITH DNA OR ACTIVATE TRANSCRIPTIONAL MACHINERY PROPERLY
      • TREATMENT IS WITH 1,25(OH) 2 D AND CALCIUM
        • RESPONSE TO THERAPY IS VARIABLE GIVEN DIVERSITY OF MOLECULAR DEFECTS (ABOVE)
  • 65. RICKETS AND OSTEOMALACIA: CAUSES, cont.
    • ANITCONVULSANT-INDUCED OSTEOMALACIA :
      • 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
  • 66. Black slide Lecture material was obtained from internet material that was put together by THOMAS P. KNECHT, M.D., Ph.D. DIVISION OF ENDOCRINOLOGY UNIVERSITY OF UTAH