Corso di Laurea di I livelloTecnici di Laboratorio Biomedico

Corso integrato FisiopatologiaUnità didattica: Fisiopatologia endocrina.

La Paratiroide

Parathyroid Gland:Think Calcium Metabolism =

Stones and Bones

CALCIUM METABOLISM

• PHYSIOLOGY OF CALCIUM METABOLISM– ORGAN SYSTEMS INVOLVED– HORMONES INVOLVED

• HYPERCALCEMIA

• HYPOCALCEMIA

• METABOLIC BONE DISEASES

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

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

CALCIUM HOMEOSTASIS

BLOOD CALCIUM

INTESTINAL ABSORPTIONORGAN PHYSIOLOGY ENDOCRINE PHYSIOLOGY

DIETARY CALCIUM

DIETARY HABITS,

SUPPLEMENTS

THE ONLY “IN”

URINETHE PRINCIPLE “OUT”

KIDNEYSORGAN PHYS.

ENDOCRINE PHYS.

BONEORGAN PHYS., ENDOCRINE PHYS.

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 1-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

NORMAL BLOOD Ca

RISING BLOOD Ca

FALLING BLOOD Ca

SUPPRESS PTH

BONE RESORPTION

URINARY LOSS

1,25(OH)2 D PRODUCTION

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.

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 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 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

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.

VITAMIN D SYNTHESIS

SKIN LIVER KIDNEY

7-DEHYDROCHOLESTEROL

VITAMIN D3

h

VITAMIN D3

25(OH)VITAMIN D

25-HYDROXYLASE

25(OH)VITAMIN D

1,25(OH)2 VITAMIN D

(ACTIVE METABOLITE)

1-HYDROXYLASE

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).

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

5’ UNTRANSLATED REGION VITAMIN D RESPONSIVE GENE

TRANSCRIPTION START SITE

RNA POLVIT D / VDR

IN THE NUCLEUS

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)

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

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

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

AGE

BONE

MASS

PEAK BONE MASS

NORMAL

FAILURE TO REACH PEAK

ACCELERATED LOSS

THEORETICAL

FRACTURE

THRESHOLD

HYPERCALCEMIA

• 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– GI, RENAL, BONE

– PTH, VITAMIN D

– TO MUCH CALCIUM ENTERING BLOOD AND/OR TOO LITTLE LEAVING BLOOD

THE STATE OF CIRCULATING CALCIUM

• CALCIUM CIRCULATES FREE (IONIC) AND PROTEIN-BOUND– ROUGHLY 50% FREE (IONIZED), AND 50%

PROTEIN BOUND AND COMPLEXED

– ALBUMIN IS THE PROTEIN RESPONSIBLE FOR MOST PROTEIN BINDING (~90%)

• IT IS RELATIVELY MEANINGLESS TO CONSIDER TOTAL CALCIUM CONCENTRA-TION WITHOUT CONSIDERING ALBUMIN CONCENTRATION

CIRCULATING CALCIUM, cont.

• IONIZED CALCIUM (FREE CALCIUM)– RESPONSIBLE FOR CALCIUM FUNCTION

– CAN BE DIRECTLY MEASURED

– GETS AROUND THE CAVEAT REGARDING SERUM ALBUMIN CONCENTRATION

• ALBUMIN CAN BE SOME DEGREE OF LOW AS A RESULT OF KIDNEY DISEASE OR LIVER DISEASE. MEASUREMENT OF IONIZED CALCIUM IN THESE STATES ACCURATELY REFLECTS CALCIUM CONCENTRATION.

– THIS IS A RELATIVELY UNDERUTILIZED TEST

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.

HYPERCALCEMIA: SIGNS AND SYMPTOMS

• CNS: altered MS, 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, shortened QT interval

CAUSES OF HYPERCALCEMIA

• HORMONAL– PRIMARY HYPERPARATHYROIDISM

– HYPERVITAMINOSIS D

– PARANEOPLASTIC (e.g., PTHrP, cytokines)

• NON-HORMONAL– RENAL FAILURE

– MILK-ALKALI SYNDROME

• DRUGS– THIAZIDES, LITHIUM, OTHERS

PRIMARY HYPERPARATHYROIDISM

• 1o 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.

PRIMARY HYPERPARATHYROIDISM

• CAUSES OF 1o 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.

PRIMARY HYPERPARATHYROIDISM

• CAUSES OF 1o HPT, cont.– FAMILIAL HYPERPARATHYROIDISM: 1o 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.

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)2D (CALCITRIOL)

• EXCESSIVE PRODUCTION OF 1,25(OH)2D– 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

HYPERVITAMINOSIS D: CLINICAL CHARACTERISTICS

• HYPERCALCEMIA• SUPPRESSED PTH

• INCREASED 1,25(OH)2D

• SOURCE– DIET?

– GRANULOMA?• SARCOIDOSIS MOST COMMON; ALSO TB, OTHERS

– LYMPHOMA?

PARANEOPLASTIC HYPERCALCEMIA

• HYPERCALCEMIA MAY BE SEEN WITH A NUMBER OF CANCERS– LUNG MOST COMMON, BUT ALSO SEEN WITH BREAST, RENAL,

LYMPHOMAS, OTHERS

• CERTAIN CANCERS MAY PRODUCE A HORMONE-LIKE FACTOR THAT ACTS IN AN ENDOCRINE FASHION, OR A FACTOR THAT ACTS IN A PARACRINE FASHION, TO CAUSE HYPERCALCEMIA, PRIMARILY BY BONE RESORPTION

• HYPERCALCEMIA CAUSED BY A “HORMONE” FROM A CANCER IS OFTEN REFERRED TO AS THE HUMORAL HYPERCALCEMIA OF MALIGNANCY

• PARANEOPLASTIC HYPERCALCEMIA IS MOST COMMON IN A SICK HOSPITALIZED PATIENT

PARANEOPLASTIC HYPERCALCEMIA: PTHrP

• PARATHYROID HORMONE RELATED PROTEIN (PTHrP) IS THE BEST CHARACTERIZED TUMOR PRODUCT THAT IS ASSOCIATED WITH THE HUMORAL HYPERCALCEMIA OF MALIGNANCY– SHARES N-TERMINAL SEQUENCE HOMOLOGY WITH PTH

• THUS THE NAME PTHrP

– BINDS TO PTH RECEPTORS• THIS RECEPTOR IS USUALLY REFERRED TO AS THE PTH/PTHrP

RECEPTOR FOR THIS REASON• MEDIATES BONE RESORPTION, RENAL Ca REABSORPTION• ASSOCIATED WITH RELATIVELY SEVERE HYPERCALCEMIA

PTHrP, cont.

• PTHrP– EXPRESSION IN NOT REGULATED BY CALCIUM OR 1,25(OH)2D

• UNREGULATED, CONSTITUTIVE EXPRESSION– NOTE THAT 1o HPT IS A SHIFT IN “SET POINT” FOR PTH

SECRETION. THE SECRETION OF PTHrP IS NOT A “SET POINT” ISSUE. THIS ACCOUNTS FOR THE FACT THAT PTHrP OFTEN CAUSES A MORE SEVERE HYPERCALCEMIA THAN 1o HPT.

– MEASUREMENT AVAILABLE IN THE CLINICAL LAB

– BIOCHEMICAL PROFILE:• HYPERCALCEMIA (often severe)

• SUPPRESSED PTH

• PTHrP ELEVATED (ASSAY CAVEATS)

• 1,25(OH)2D USUALLY NORMAL (NOT AS HIGH AS IN 1o HPT)

PTHrP INTERACTIONS

TUMOR

PTHrP

BONE: resorption

KIDNEY: tubular reabsorption

HYPERCALCEMIA

PARATHYROIDS:

suppress PTH secretion

NOTE: NO FEEDBACK LOOPS TO TUMOR

MULTIPLE MYELOMA

• ONE OF THE FIRST CANCERS RECOGNIZED TO CAUSE HYPERCALCEMIA– THE FACTOR IS NOT WELL CHARACTERIZED, AND

APPEARS TO BE MEDIATED BY A FAMILY OF CYTOKINES (PREVIOUSLY REFERRED TO AS OSTEOCLAST ACTIVATING FACTOR’S or OAF’s)

– BIOCHEMICAL PROFILE• HYPERCALCEMIA

• SUPPRESSED PTH

• NORMAL PTHrP

• NORMAL OR LOW 1,25(OH)2D

NON-HORMONAL HYPERCALCEMIA

• MILK-ALKALI SYNDROME:– INTAKE OF HIGH DOSES OF CALCIUM AND

ABSORBABLE ANTACID (SUCH AS NaCO3)

– RARE CAUSE OF HYPERCALCEMIA NOW• MORE COMMONLY DESCRIBED IN EARLIER PART OF 20TH

CENTURY (NO H2 BLOCKERS OR PPI’S!!)

– MECHANISM NOT ABSOLUTELY CLEAR:• INCREASED INTESTINAL ABSORPTION• DECREASED RENAL CLEARANCE

– PTH SUPPRESSED, PTHrP NORMAL, 1,25(OH)2D NORMAL

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)2D

• EXOGENOUS 1,25(OH)2D MAY CONTRIBUTE TO HYPERCALCEMIA

– CALCIUM AND PHOSPHATE RENAL CLEARANCE IS ABOLISHED, AND DIALYSIS DOES A RELATIVELY POOR JOB AT CLEARANCE (COMPARED TO, SAY, POTASSIUM)

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, 1o HPT, ETC.

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)

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)2D

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

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.

HYPOCALCEMIA: SIGNS AND SYMPTOMS

• NEUROMUSCULAR: INVOLUNTARY MUSCLE CONTRACTION (TETANY), 7TH 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

CAUSES OF HYPOCALCEMIA

• HYPOPARATHYROIDISM– POSTSURGICAL (MOST COMMON)– AUTOIMMUNE– PSEUDOHYPOPARATHYROIDISM (PTH RESISTANCE)– IDIOPATHIC

• HYPOVITAMINOSIS D– DIETARY DEFICIENCY– RICKETS (RACHITISMO), 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

– VITAL IMPORTANCE OF EXCELLENT SURGEON EXPERIENCED IN THYROID AND PARATHYROID SURGERY

• AUTOIMMUNE – MAY CLUSTER WITH OTHER AUTOIMMUNE ENDOCRINE

DISEASES, INCLUDING IDDM, AUTOIMMUNE THYROID DISEASE, ADDISON’S, ETC. THIS IS RATHER UNCOMMON.

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

DEFECTIVE VITAMIN D FUNCTION

• CLINICAL SYNDROMES BROADLY CATEGORIZED AS RICKETS (rachitismo) AND OSTEOMALACIA.

• DIMINISHED GI ABSORPTION OF Ca

• TENDENCY TOWARD HYPOCALCEMIA– SECONDARY HYPERPARATHYROIDISM

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

SECONDARY HYPERPARATHYROIDISM

• CAUSES: UNLIKE 1o HPT, WHICH IS A PRIMARY DYSFUNCTION OF PARATHYROID TISSUE, 2o 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.)

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

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

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)2D, AND INCREASED ALKALINE PHOSPHATASE

– TREATMENT IS BY GIVING 1,25(OH)2D AND CALCIUM

RICKETS AND OSTEOMALACIA: CAUSES, cont.

• TISSUE RESISTANCE TO 1,25(OH)2D– AUTOSOMAL RECESSIVE, OR ACQUIRED

– DEFECT IN NUCLEAR RECEPTOR FOR VITAMIN D• 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

• RESPONSE TO THERAPY IS VARIABLE GIVEN DIVERSITY OF MOLECULAR DEFECTS (ABOVE)

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