Download Disorders of Ca/phosphate homeostatsis: Hyper

Disorders of Ca/phosphate
homeostatsis:
Hyper- and hypocalcemias and the
osteoporosis
Kádár Kristóf
Deparment of Oralbiology
2016
Calcium and Phosphate – Why is it
important?
• Phosphate is component of DNA, RNA, ATP,
phospholipids, and pH buffers
– ~750 g in adult skeleton
– plasma concentration is 0.81-1.45 mmol/L
– 2 plasma forms: HPO42- and H2PO4-
• Calcium needed in neurons, muscle
contraction,blood clotting and exocytosis
–
–
–
–
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~1100 g (28.6 mol) in adult skeleton
plasma concentration is ~ 2.5 mmol/L
In blood, 50% of Ca2+ binds to albumin
Plasma ionized (free) Ca2+ level: 1.1-1.4 mmol/L.
ionized (free) Ca2+biological effect (regulation signal)
Calcium and Phosphate – Why is it
important FOR A DENTIST?
• Complex and robust regulation exist to maintain ion
levels in the physiological range
• Main components of the mineralized tissue
• Chronic imbalances of phosphate/calcium regulation
results in the altered composition and mechanical
properites of the hard tissues!
Ion Imbalances
• Changes in phosphate levels  little effect
– chronic changes in phosphate levels→ changes in serum calcitriol,
PTH, FGF23,
– Ca2+
• Changes in calcium can be serious even life threatening
– hypocalcemia is deficiency of blood calcium (causes excitability of
nervous system if too low)
• Patomechanism: with less calcium, sodium channels open more easily,
sodium enters cell and excites neuron
• muscle spasms, tremors or tetany ~ 1.5 mmol/L
• laryngospasm and suffocation ~ 1.0 mmol/L
– hypercalcemia is excess of blood calcium
• Patomechanism: binding to cell surface makes sodium channels less likely
to open, depressing nervous system
• muscle weakness and sluggish reflexes, cardiac arrest ~ 3.0 mmol/L •
• Calcium/phosphate homeostasis depends on calcitriol,calcitonin,
PTH and FGF23 regulation
Hormonal control of calcium balance
7-Dehydrocholesterol
+
UV light (skin)
vitamin D3
kidney
PTH
+
liver
+
-
25(OH)D3
Prostate, breast,
colon, ß-cells etc.
+
FGF23
+
1,25(OH)D3
autocrine effects:
1,25(OH)D3
endocrine effects:
+
1,24,25(OH)D3
inactive!
Calcitriol (activated vitamin D)
• Acts through the regulation of gene
expression – VDR receptor
• Calcitriol behaves as a hormone that raises
blood calcium concentration
– Increases intestinal absorption (calbindin, TRPV6)
and absorption from the skeleton
– increases stem cell differentiation into osteoclasts
– promotes urinary reabsorption of calcium ions
• Abnormal softness (rickets) in children and
(osteomalacia) in adults without vitamin D
Parathyroid Hormone
• Glands on posterior surface of thyroid
• Se [Ca2+]↓  CaSR  PTH↑
• Main endocrine eunction  raise calcium blood level
(Classical targets: osteblast, osteoclast, chondrocyte, renal tubular cells)
– causes osteoblasts to release osteoclaststimulating factor (RANKL) increasing osteoclast population
– promotes calcium resorption by the kidneys
– promotes calcitriol synthesis in the kidneys (activates 1(OH)-ase)
– inhibits phospahte reabsorption in the kidneys (inhibits SLC34A1,
SLC34A3)
– inhibits collagen synthesis and bone deposition by osteoblasts
• Non-classical target cells:
– smooth muscle (relaxation → hypotensive effect)
– cardiomyocytes (hypertrophy – eg. LVH in dialysed patients)
– sinus node (positive chronotropic effect)
FGF-23
• Fibroblast growth factor-23
• Produced mainly by bone and connective tissue
• Effects
– In the kidney
• inhibits tubular P reuptake – phosphaturia
• inhibits 1α-hydroxilase activity
– Induces 24-hydroxilase activity (calcitriol ↓) – indirectly decreases P
absorption
• Other effects
– Parathyroids:
• directly inhibits PTH secretion
– Cardiac:
• directly induces cardiac hypertrophy
• FGF23 mRNA expression is stimulated by:
– calcitriol
– hyperphosphataemia (indirect effect)
The regulation of calcium and phosphate homeostasis
by PTH, vitamin D and FGF23
DiGirolamo, D. J. et al. (2012) The skeleton as an endocrine organ Nat. Rev. Rheumatol. doi:10.1028/nrrheum.2012.157
Calcitonin
• Secreted (C cells of thyroid gland) when calcium
concentration rises too high
• Functions
– reduces osteoclast activity as much as 70%
– increases the number and activity of osteoblasts
• Important in children, little effect in adults
– osteoclasts more active in children
– deficiency does not cause disease in adults
• Reduces bone loss in osteoporosis
Other hormones and local factors
•
Hormones
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•
Factors presumedly produced by the osteoblasts:
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–
–
–
•
insulin
growth hormone (GH)
glucocorticoids
testosterone, oestrogen
thyroid hormones
IGF I
FGF
PDGF
TGFb
Factors produced by chondrocytes
– IGF I
– bFGF
– TGFb
•
Factors produced by blood cells
– IL-1, IL-6
– Colony stimulating factors
– TNF
Main controlling mechanisms of calcium
homeostasis
Calcium balance
Causes of hypocalcemia
Hypoparathyroidism
Etiology
• Surgical
Hypoparathyroidism
• Idiopathic
Hypoparathyroidism
multi endocrine
deficiencyautoimmunecandidiasis (MEDAC)
• Functional
Hypoparathyroidism
(low magnesium
intake, malabsorption)
Clinical features of hypoparathyroidism
• Neuromusclar manifestation
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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
Clinical symptomes of hypocalcemic states
Etiologies of hypercalcemia
Increased GI Absorption
•
•
Milk-alkali syndrome
Elevated calcitriol
– Vitamin D excess: Excessive dietary intake, granulomatous disease
– Elevated PTH
– Hypophosphatemia
Increased loss from bone
•
Increased net bone resorption
– Elevated PTH: Hyperparathyroidism (ie. primary hyperparathyroidism)
•
Malignancy
– Osteolytic metastases, PTHrP secreting tumor, multiple myeloma
Increased bone turnover
– Paget’s disease, hyperthyroidism
Decreased bone mineralization
•
•
Elevated PTH, aluminum toxicity
Decreased urinary excretion
•
Thiazide diuretics, elevated calcitriol, elevated PTH
Consequences of hypercalcemia
• Gastrointestinal
– obstipatio, nausea, vomitting; ileus, abdominal pain
– ulcus pepticum, pancreatitis, anorexia
– polydipsia
• Renal
– hypercalciuria, polyuria (Na and K loss), nycturia, albuminuria
– nephrolithiasis, nephrocalcinosis, azotaemia, renal insufficiency
• Neural
– emotional instability, delirium, psychosis
– neuromuscular disorders, muscle weakness
• Circulation
– hypertension, short QT, impulse formation and conduction
problems
Hyperparathyroidism (PTH↑)
•
Primary hyperparathyroidism
– Parathyroid adenoma
– PTH producing tumor (MEN)
– Lab param.: se Ca ↑, se P ↓
•
Secondary hyperparathyroidism
– Reactive PTH overproduction (cause: hypocalcaemia)
– eg. kidney insufficiency
– Lab param.: se Ca ↑, se P ↑
•
Tertiary hyperparathyroidism
– After a long period of secondary hyperparathyrosidism in patients with kidney
insufficiency
– autonomous PTH hypersecretion, no response to drugs
– Therapy: surgical removal (3 + half gland)
– Lab param.: se Ca ↑, se P ↑
Primary hyperparathyroidism
Increased resorption of bone
surfaces Increased number of
osteoclasts, osteocytic osteolysis
Consequences of hypercalcemia
• Gastrointestinal
– obstipatio, nausea, vomitting; ileus, abdominal pain
– ulcus pepticum, pancreatitis, anorexia
– polydipsia
• Renal
– hypercalciuria, polyuria (Na and K loss), nycturia, albuminuria
– nephrolithiasis, nephrocalcinosis, azotaemia, renal insufficiency
• Neural
– emotional instability, delirium, psychosis
– neuromuscular disorders, muscle weakness
• Circulation
– hypertension, short QT, impulse formation and conduction
problems
Dental signs and symptoms
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Increased calcium levels in the saliva
Increased calculus formation
Widening of the periodontal space
Absence of lamina dura
Cystic lesions in the jawbone; filled with granulomatous
tissue - epulis
Familial hypocalciuric hypercalcemia
(FHH)
• Genetic, autosomal dominant
• Mimics primary hyperparathyroidism
• PTH slightly high, however inappropriate for level of
calcium
• Mutation in parathyroid calcium sensor
– Higher setpoint
• Low urinary calcium/creatinine <0.01
• No end organ damage
• No treatment required
Malignancy associated hypercalcemia
• Most common cause of hypercalcaemia in hospitalized patients
• Humoral hypercalcaemia (paraneoplastic)
– Tumor cells may secrete:
• PTH, PTHrP
• 1,25(OH)D3
• RANKL
– Epithelial cc (lung, cervix); bladder cancer; ovarial cancer; lymphomas; multiple
myeloma
• Local osteolytic hypercalcaemia
– Direct osteolytic effetc of tumor metastases in the bones
• PTHrP (PTH-related Protein)
– structure similar to PTH, same receptor, autocrine/paracrine effects
– not synthesized in parathyroids, no role in endocrine regulation of Ca-P
– Physiological importance: fetal and neonatal bone development
– Produced in uterus and placenta of pregnants, and in lactating breast
– Pathology: secreted by bronchial-, breast-, kidney-, bladder-, esophageal
cc. cells
Granulomatous disease
• Sarcoidosis, Tuberculosis, Leprosy
• Activation of 1 alpha hydroxylase (macrophage)
– conversion 25-OH Vitamin D  increased level of 1,25(OH)
Vitamin D
• PTH low
• Treatment: glucocorticoids
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
Milk-alkali syndrome (Burnett’s syndrome)
• Hypercalcemia from excess ingestion alkali
and calcium
– Excessive Milk or calcium supplements
– Excessive soluble alkali (absorbable antacid)
– Sodium bicarbonate, calcium carbonate
– Potentiated by Vitamin D supplementation
• Chronic milk-alkali leads to renal
insufficiency
– Soft tissue calcification of kidneys
– Nephrocalcinosis
Milk-alkali syndrome (Burnett’s syndrome)
Usually peptic ulcer, or
similar complaints
P homeostasis
Etiologies of Hyperphosphatemia
• Increased GI intake
– Fleet’s phospho-soda
• Decreased urinary excretion
– Renal failure
– Low PTH (hypoparatyrodism)
• after thyroidectomy, after I131 treatment, autoimmune
• Cell lysis
– Rabdomyolysis
– Tumor lysis syndrome
Etiologies of Hypophosphatemia
• Decreased GI Absorption
– Decreased dietary intake (rare in isolation)
– Diarrhea / Malabsorption
– Phosphate binders (calcium acetate, Al & Mg containing antacids)
• Decreased bone resorption / Increased bone
mineralization
– Vitamin D deficiency / low calcitriol
– Hungry bones syndrome
– Osteoblastic metastases
• Increased urinary excretion
– Elevated PTH (as in primary hyperparathyroidism)
– Vitamin D deficiency / low calcitriol
– Fanconi syndrome
• Internal redistribution
FGF-23 and its role in the phosphate
homeostasis
• Fibroblast growth factor-23
• Produced mainly by bone and connective tissue
• Effects
– In the kidney
• inhibits tubular P reuptake – phosphaturia
• inhibits 1α-hydroxilase activity
– Induces 24-hydroxilase activity (calcitriol ↓)
• FGF23 mRNA expression is stimulated by:
– calcitriol
– hyperphosphataemia (indirect effect)
Regulation of FGF-23
FGF23 induced disorders of
phosphate metabolism
• Common: FGF23↑
• Symptoms:
– hypophosphataemia, low calcitriol level, BMD↓ (bone density)
• Genetic diseases:
– X-linked hypophosphataemia (XLH)
• Mutation of PHEX gene, inactive PHEX protein /1:20000/)
– (PHEX: „phosphate-regulating gene with homologies to endopeptidases on
the X-chromosome”)
• Function of PHEX: inactivates FGF23 (indirect effect)
– Autosom. dom. hypophosphataemic ricketts (ADHR)
• rare; mutant FGF23, resists proteolysis: high circulating FGF23 levels
• Tumor induced osteomalacia (TIO)
– Mainly benign mesenchymal tumors produce FGF23
Metabolic bone diseases
Normal
Matrix
Minerals
Osteoporosis
Osteomalacia
Combined
Model of risk factors
Osteoporosis
A systemic skeletal disease characterized by low bone mass and
microarchitectural deterioration of bone tissue, with a consequent
increase in bone fragility and susceptibility to fracture.
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Chronic pain
Height loss
Kyphosis
Decreased self-esteem
Restrictive lung dx
Constipation, abdominal pain
Depression
Trabecular structure in osteoporosis
Importance of osteoporosis
Risk factors for osteoporotic fractures:
• Hypogonadism in men
• Personal history of fracture as an adult
• Alcoholism
• History of fracture in a first degree relative
• Current cigarette smoking
• Caucasian
• Low calcium intake (lifelong)
• Female
• Inadequate physical activity
• Low body weight (<55 kg)
• Dementia
Estrogen deficiency
• Recurrent Falls
Early menopause (<age 45)
• Poor health/frailty
Bilateral oopherectomy
Prolonged amenorrhea (>1 yr)
Classification of ostoporosis
Primary
• Postmenopausal
– Decreased estrogen results in increased osteoclastic activity
without increased osteoblastic activity
– Bone loss – 2-3% per year of total bone mass
– Most common fx: vertebral, distal forearm
• Age related – 3rd decade of life starts slow decline in
bone mass at rate of 0.5-1% per year
– Most common types of fx: hip and radius
– F>M
Secondary
Risk factors of osteoporosis
Pathogenesis of Type I osteoporosis
Pathogenesis of Type II osteoporosis
Osteomalatia
Vitamin D – the dentists point of view
• D – vitamin overdose
» Hypoplastic enamel
(if during tooth development )
• D – vitamin deficinecy
- Dentin: dentinmatrix problems
(irregular dentin-predentin interface)
- Enamel: thin, decreased mineralization,
irregular surface;