Disorders of Calcium Metabolism презентация

Содержание

Calcium An essential intracellular and extracellular cation Extracellular calcium is required to maintain normal biological function of nervous system, the musculoskeletal system, regulation of neuromuscular contractility and blood coagulation Intracellular calcium

Слайд 1Disorders of Calcium Metabolism
Elena Segal
Rambam Medical Center
Haifa

Слайд 2Calcium
An essential intracellular and extracellular cation
Extracellular calcium is required to maintain

normal biological function of nervous system, the musculoskeletal system, regulation of neuromuscular contractility and blood coagulation
Intracellular calcium is needed for normal activity of many enzymes.
Regulation of endocrine and exocrine secretory activities: insulin, aldosterone
Activation of compliment system
Bone metabolism: calcium salts provide structural integrity of the skeleton ( mineralization)


Слайд 3
calcium
40-45 %
ionized
40-45 %
albumin
bound
10%
complexed
citrate, sulphate
8.5–10.5 mg/dl
ECF



Filtration
5-7gr
Reabsorption
4.9-6.7gr
98%
Diet 0.5-1.5 gr
Absorption
0.25-0.5gr
Secretion
0.1-0.2gr
Feces
0.35-0.6gr
Resorption
0.3-0.5 g


Formation
0.3-0.5 g

Bone
1000

g

0.15-0.3 g/24h

Total body Ca
1 to 1.5 kg
99%- skeleton
0.1% ECF
rest intracellular

Слайд 4Calcium and Albumin
40-45% of circulating calcium is bound to albumin
Change

in serum albumin change in measured total serum calcium concentration
Calcium is bound to carboxyl groups in albumin, this binding is highly pH dependent
Acute acidosis binding ionized calcium
Acute alkalosis binding ionized calcium
A shift of 0.1 pH unit produces a change in ionized calcium of 0.04 to 0.05 mmol/L ( 0.16-0.2 mg/dl)
These changes are not reflected at the total calcium









Слайд 5Calcium and Albumin
At pH 7.4 each g/dl of serum albumin binds

0.8 mg/dl of calcium
Serum calcium should be “corrected” according to serum albumin level
Normal level of serum albumin is 4 g/dl
Change of 1 g/dl in serum albumin 0.8 mg/dl in total serum calcium
Example: A patient with total serum calcium 7.5 mg/dl albumin 2 g/dl, has corrected serum calcium of 9.1 mg/dl





Ca = SerumCa + 0.8 * (NormalAlbumin - PatientAlbumin)

Слайд 6Disorders of Calcium Metabolism
Hypercalcemia Serum Calcium >10.4 mg/dl
Hypocalcemia

Serum Calcium < 8.5 mg/dl


Слайд 7Causes of hypercalcemia
PTH-mediated
Primary hyperparathyroidism (sporadic) –solitary adenoma or hyperplasia
Familial MEN1

and -2a
FHH
Tertiary hyperparathyroidism (renal failure)

PTH-independent
Hypercalcemia of malignancy:
PTHrp
Activation of extrarenal 1 alpha-hydroxylase (increased calcitriol)
Osteolytic bone metastases and local cytokines

Слайд 8Causes of hypercalcemia
Vitamin D intoxication
Chronic granulomatous disorders: Activation of extrarenal 1

alpha-hydroxylase (increased calcitriol)
Medications :
Thiazide diuretics
Lithium
Teriparatide
Excessive vitamin A
Theophylline toxicity


Associated with high bone turnover
Hyperthyroidism
Immobilization
Acromegaly
Miscellaneous Pheochromocytoma Adrenal insufficiency Parenteral nutrition
Milk alkali syndrome

Слайд 9Diagnosis of Hypercalcemia

Serum Ca ↑
Measure serum albumin
or ionized calcium
Albumin corrected

calcium normal

Medical history
and medication use history

Measure PTH

PTH ↑ or N

Check calciuria


PTH ↓

Malignancy

Check 1,25(OH)2D3


If high- Primary HPT; if low FHH

Lymphomas

Слайд 10Manifestations of hypercalcemia

Слайд 11Renal manifestations
The most important renal manifestations are polyuria, resulting from decreased

concentrating ability in the distal tubule, nephrolithiasis, and acute and chronic renal insufficiency.

Nephrogenic diabetes insipidus — Chronic hypercalcemia leads to a defect in concentrating ability that may induce polyuria and polydipsia in up to 20 percent of patients. The mechanism is incompletely understood, but the downregulation of aquaporin-2 water channels receptors, and calcium deposition in the medulla with secondary tubulointerstitial injury and impaired generation of the interstitial osmotic gradient may play important roles.


Слайд 12Renal manifestations
Nephrolithiasis — When hypercalcemia is due to primary hyperparathyroidism or

sarcoidosis, it is often longstanding, and the resulting chronic hypercalciuria may cause nephrolithiasis. Increased calcitriol production may also play an important role in both diseases.

Renal tubular acidosis — Chronic hypercalcemia causes type 1 (distal) renal tubular acidosis .The ensuing hypercalciuria and hypocitraturia can contribute to the development of nephrolithiasis.

Слайд 13Gastrointestinal manifestations
Nausea.
Constipation may be related to decreased smooth muscle tone

and/or abnormal autonomic function.
Peptic ulcer disease has been described in patients with hypercalcemia due to primary hyperparathyroidism and may be caused by calcium-induced increases in gastrin and acid secretion.
Pancreatitis due to deposition of calcium in the pancreatic duct and calcium activation of trypsinogen within the pancreatic parenchyma

Слайд 14Cardiovascular symptoms
Shortened QT interval
Ventricular arrhythmias
ST-segment elevation mimicking myocardial
Long-standing hypercalcemia,

as occurs in primary hyperparathyroidism, can lead to other cardiac abnormalities, including deposition of calcium in heart valves, coronary arteries, hypertension; and cardiomyopathy.

Слайд 15Hyperparathyroidism

Secondary hyperparatroidism: due to vitamin D deficiency; renal failure

Tertiary hyperparathyroidism: in longstanding renal failure

Слайд 16Primary Hyperparathyroidism
Incidence 1/1000- 42/100 000
Postmenopausal women 1/200;
↑ X 3.0 in

women then in men;
At age 70-79 21:1000
80% single gland involvement – adenoma
20% multiple gland involvement – hyperplasia
<2% carcinoma
MEN


Слайд 17or multiple adenomas, nearly 100%
15-20%
up to 60%
nearly 100%
30-100%
10-25%

Слайд 18Clinical Manifestations of Prim Hyperparathyroidism
CNS - Cognitive difficulties, apathy, drowsiness, obtundation

or even coma
GI - Anorexia, nausea, vomiting, constipation and rarely acute pancreatitis
CVS - Hypertension, A-V nodal delay, shortened QT interval, enhanced sensitivity to digitalis, compete heart block, ventricular arrhythmias
RENAL- Loss of concentrating ability, polyuria, polydipsia, nephrolithiasis and occasionally nephrocalcinosis, nocturia


Слайд 19Bone and Joint Manifestations in Primary Hyperparathyroidism
Osteoporosis
Diffuse bone pain
Osteitis fibrosa cystica
Diffuse

demineralization
Subperiostal bone resorption
Phalanges
Lamina dura
Distal clavicles


Cystic lesions
Brown tumors
Cysts
Deformities, Fractures, Pain
Arthritic symptoms
Resorption of articular bone
Periarticular metastatic calcification
Pseudogout
Gout


Слайд 22Treatment
When is surgery indicated in PHPT patients
?

Слайд 23Guidelines for Surgery


Слайд 24Other Considerations
Neuropsychological disturbances
Weakness and easy fatigability
Depression
Intellectual weariness
Increased sleep requirements
Improved by surgery
Onset

of Menopause
Increased bone loss


Слайд 25US in the diagnosis of PTA

Слайд 2699mTc- sestamibi Parathyroid Scan


20 min
3 hours
90% sensitivity in parathyroid
tissue detection

Слайд 27What is 4D-CT?
4D-CT includes image sets in three planes (axial, coronal,

sagittal) from the angle of mandible to the mediastinum.The “fourth” dimension of 4D-CT is the perfusion information derived from multiple contrast phases.
It is most commonly performed with three phases: non-contrast, arterial, and delayed phase imaging .

Слайд 284D CT in diagnosis of PHPT
Arterial phase images are acquired 25

seconds after the start of the injection and the delayed (venous) phase are acquired 80 seconds from the start of the injection.

Слайд 29Patients who weren‘t operated- Monitoring guidelines

Слайд 30General Measures
Hydration
Adequate Mobility
Diet neither restrictive nor excessive in calcium
Adequate vitamin D

status
Prompt medical attention for the possibility of worsening of hypercalcemia (intercurrent illness accompanied by risk of dehydration)


Слайд 31Calcium-sensing Receptor
A member of the G protein-coupled receptor family
Contains seven

hydrophobic helices that anchor it in the plasma membrane. The large (~600 amino acids) extracellular domain - critical to interactions with extracellular calcium
Large (~200 amino acids) cytosolic tail.


Слайд 32Inactivating Mutations in Calcium Sensing Receptor
Inactivating mutation
Familial hypocalciuric hypercalcemia (FHH) -

heterozygous
Calcium set point serum calcium
Urinary calcium reabsorption urinary
calcium
Neonatal severe hyperparathyroidism (NSHPT) – homozygous
parathyroid


Familial hypocalciuric hypercalcemia (FHH) - heterozygous
Calcium set point serum calcium
Urinary calcium reabsorption urinary
calcium
Neonatal severe hyperparathyroidism (NSHPT) – homozygous-incompatible with life if not resect the parathyroid



No need for parathyroid surgery in FHH!!

Слайд 33Hypercalcemia of Malignancy
Lung, breast, and prostate cancer frequently invade skeleton and

destroy bone tissue
Damage to skeleton usually late in course of disease
Bone damage associated with considerable worsening in patient’s quality of life
Multiple myeloma has skeletal complications in virtually 100% of cases
Breast and lung cancer also cause hypercalcemia of malignancy, without invading skeleton


Слайд 34PthrP Induced Hypercalcemia
Squamous cell carcinoma
Islet cell tumor (pancreas)
Adult T cell leukemia
Renal

cell carcinoma
Breast carcinoma


Слайд 35PTHrP-PTH related peptide
Gen located on the chromosome 12
Gen is expressed in

the embrional tissues: cartilage, heart, epithelium, hear bulbs
Expression of the PTHrP gen in adult: plays role in breast development; presents in breast milk in high concentration
Mutation in embryo:
Heterozygous are normal
Homozygous –lethal mutation with major bone and cartilage abnormalities



Слайд 36Treatment
Hydration
Bisphosphonates IV, Denosumab
Calcitonin
Glucocorticoids
Dialysis

Слайд 37Hydration
First step in the management of severe hypercalcemia - Isotonic saline
Usually

↓ serum calcium by 1.6-2.4mg/dl
Hydration alone rarely leads to normalization in severe hypercalcemia
Rate of IV saline based on severity of hypercalcemia and tolerance of CVS for volume expansion, if possible achieve urine output of 300 ml/hr, that is then adjusted to maintain the urine output at 100 to 150 mL/hour.


Слайд 38Loop Diuretics
In the past intensive administration of furosemide was used (80

to 100 mg every one to two hours).
It needs aggressive fluid hydration (10 liters daily), saline therapy beyond that necessary to restore euvolemia.
Now use of calcitonin and bisphosphonates is more effective.


Слайд 39Calcitonin
The efficacy of calcitonin (4 IU/kg every 6-12 hours) is limited

to the first 48 hours, due to development of tachyphylaxis, perhaps due to receptor downregulation .
Calcitonin and hydration provide a rapid reduction in serum calcium concentration, while a bisphosphonate provides a more sustained effect.


Слайд 40Bisphosphonates
Structurally related to pyrophosphate
Great affinity for bone and their resistance to

degradation
Bind to hydroxyapatite in bone and inhibit the dissolution of crystals
Extremely long half life in bone
Poor GI absorption < 1%


Слайд 41Zoledronic Acid (ZOMERA)
Zoledronic acid belongs to a new class of highly

potent bisphosphonates
Heterocyclic, nitrogen-containing bisphosphonate composed of:
A core bisphosphonate moiety
An imidazole-ring side chain containing 2 critically positioned nitrogen atoms


Слайд 42Denosumab Mechanism of Action
© 2007 Amgen. All rights reserved.

RANKL
RANK
OPG Denosumab

Bone Formation

Hormones Growth factors
Cytokines
Bone

Resorption Inhibited

Osteoclast Formation, Function, and Survival Inhibited

CFU-GM

Pre-Fusion Osteoclast

CFU-GM=colony forming unit granulocyte macrophage

Provided as an educational resource. Do not copy or distribute.

© 2007 Amgen. All rights reserved.

Osteoblasts


Calcium nadir 8-11 days after injection

Слайд 43Inhibit the growth of neoplastic lymphoid tissue
Counteract the effects of vitamin

D

Glucocorticoids


Слайд 44
Low PTH Hypocalcemia

Слайд 45Hypocalcemia
Low PTH (hypoparathyroidism)
Genetic disorders: Abnormal parathyroid gland development
Abnormal PTH

synthesis; Activating mutations of calcium-sensing receptor (autosomal dominant hypocalcemia)
Post-surgical
Autoimmune: Autoimmune polyglandular syndrome (associated with chronic mucocutaneous candidiasis and primary adrenal insufficiency)
Hypoparathyroidism due to activating antibodies to calcium-sensing receptor
Infiltration of the parathyroid gland (granulomatous, iron overload, metastases)
Radiation-induced destruction parathyroid glands
Hungry bone syndrome (post parathyroidectomy)

Слайд 46Hypocalcemia
High PTH (secondary hyperparathyroidism in response to hypocalcemia)
Vitamin D deficiency

or resistance
Parathyroid hormone resistance: Pseudohypoparathyroidism
Hypomagnesemia
Renal disease
Loss of calcium from the circulation:
Hyperphosphatemia ; Tumor lysis ; Acute pancreatitis (the mechanism unknown)
Osteoblastic metastases; Acute respiratory alkalosis
Sepsis or severe burns- the cause appears to be a combination of impaired secretion of PTH coupled with reduced calcitriol production

Слайд 47Drugs induced hypocalcemia
Inhibitors of bone resorption (bisphosphonates, calcitonin, denosumab), especially in

vitamin D deficiency
Cinacalcet –calcimimetic
Calcium chelators (EDTA, citrate, phosphate) Foscarnet (due to intravascular complexing with calcium)
Phenytoin (due to conversion of vitamin D to inactive metabolites)
Fluoride poisoning

Слайд 48Trousseau's sign is the induction of carpopedal spasm by inflation of

a sphygmomanometer above systolic blood pressure for three minutes.
Chvostek's sign is contraction of the ipsilateral facial muscles elicited by tapping the facial nerve just anterior to the ear

Hypocalcemia

Слайд 49Hypocalcemia: Carpopedal spasm and ECG changes
Carpopedal Spasm


Sinus rhythm with diffuse T

wave inversion
QT prolongation (The corrected qtc is 560 ms )
Prolongation is in the ST segment rather than the T waves

Слайд 50Treatment of Acute Hypocalcemia
Promptly correct symptomatic or severe hypocalcemia with cardiac

arrhythmias or tetany with parenteral administration of calcium salts with IV calcium therapy.
IV calcium therapy is suggested in asymptomatic patients with an acute decrease in serum corrected calcium to ≤7.5 mg/dL
(1 to 2 g of calcium gluconate, equivalent to 90 to 180 mg elemental calcium, in 50 mL of 5 percent dextrose) can be infused over 10 to 20 minutes. Is effective for 2-3 hours



Слайд 51Treatment of Acute Hypocalcemia
For those with milder symptoms of neuromuscular irritability

(paresthesias) and corrected serum calcium concentrations greater than 7.5 mg/dL initial treatment with oral calcium supplementation is sufficient. If symptoms do not improve with oral supplementation, intravenous calcium infusion is required.
To effectively treat hypocalcemia in patients with concurrent magnesium deficiency,hypomagnesemia should be corrected first.

Identify and treat the cause of hypocalcemia and taper the infusion.

Слайд 52To prevent Hypocalcemia due to Hungry bone syndrome
Start oral calcium and

vitamin D treatment early. Patients with postparathyroidectomy hungry bone disease, especially those with osteitis fibrosa cystica, can present with a dramatic picture of hypocalcemia.

Слайд 53
Primary hypoparathyroidism

Слайд 58Natpara
Natpara- for use in patients who
can’t be normalized on regular


oral therapy, or have complication
s due to it (nephrolithiasis, hyper
Calciuria)

Слайд 59Causes of magnesium depletion
Causes of magnesium depletion
Renal losses
Gasro-intestinal losses


Слайд 60Treatment of Hypomagnesemia

If the serum magnesium concentration is low, 2 g

(16 mEq) of magnesium sulfate should be infused as a 10 percent solution over 10 to 20 minutes, followed by 1 gram (8 mEq) in 100 mL of fluid per hour.

Magnesium repletion should be continued as long as the serum magnesium concentration is less than 0.8 mEq/L (1 mg/dL or 0.4 mmol/L).

Persistent hypomagnesemia, as occurs in some patients with ongoing gastrointestinal (malabsorption) or renal losses, requires supplementation with oral magnesium, typically 300 to 400 mg daily divided into three doses.

Слайд 61Treatment of Hypomagnesemia

Oral repletion- if available and tolerable.
A typical daily

dose in a patient with normal renal function is 240 to 1000 mg (20 to 80 meq [10 to 40 mmol]) of elemental magnesium in divided doses.
If a sustained-release preparation is not available, magnesium oxide 800 to 1600 mg (20 to 40 mmol [40 to 80 meq]) daily in divided doses may be used for moderate to severe hypomagnesemia.
Diarrhea frequently occurs with magnesium oxide therapy.

Слайд 62Thank you and Good luck!

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