Hormonal Control of Calcium and Phosphate: Part 2 Flashcards
Hypocalcemia
low serum calcium
Hypercalcemia
high serum calcium
Hypophosphatemia
low serum phosphate
Hyperphosphatemia
high serum phosphate
Calcium and Phosphate Homeostasis can be
Disrupted in Many Different ways: (7)
•Dietary deficiency or excess of calcium, (phosphate), vitamin D
•Mutations in genes for Vitamin D receptor, 25-OH-vitamin D 1α-
hydroxylase enzyme
•Elevated or decreased PTH (parathyroid tumors, CaSR mutations,
agenesis of parathyroid glands, loss of parathyroid tissue due to
thyroid surgery)
•Insensitivity of tissues to PTH (inactivating mutations in G-proteins
important for PTH receptor signaling)
•Mutations in phosphate transporter molecules (NaPi-IIc)
•Mutations in FGF23 or regulators of FGF23 (Dmp1, PHEX)
•Chronic kidney disease
Chronic kidney disease affects Ca2+ /Pi homeostasis because
impaired kidney function interferes with Ca2+ and Pi reabsorption
Hypocalcemia - blood calcium concentration…
below normal range (<1.1-1.35 mM ionized calcium)
Symptoms of hypocalcemia (depending on rapidity of onset and whether hypocalcemia is mild or severe): (6)
- Muscle cramping
- Muscle spasms
- Increased neuromuscular excitability
- Fatigue
- Cardiac dysfunction
- Depression, psychosis, seizures
causes of hypocalcemia (6)
inadequate PTH production
syndromes with component of hypoparathyroidism
PTH resistance
inadequate vitamin D
vitamin D resistance or synthesis defects
miscellaneous
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Inadequate PTH production examples (7)
•PTH gene mutations
•Hypoparathyroidism due to parathyroid agenesis/X-linked
hypoparathyroidism
•Parathyroidectomy as a complication of thyroid surgery
•Constitutively active CaSR mutations (OMIM# 601198)
(autosomal dominant hypocalcemia)
•Autoimmune (e.g. Antibodies that activate the CaSR)
•Post radiation therapy
•Tumors that metastasize to parathyroid
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Syndromes with component of hypoparathyroidism examples (5)
•DiGeorge syndrome •HDR (hypoparathyroidism, deafness, renal anomalies) syndrome •Kenney-Caffey syndrome •Sanjad-Sakati syndrome •Kearns-Sayre syndrome
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Vitamin D resistance or synthesis defects
(Vitamin D dependent Rickets) example (1)
•Mutations in VDR or 1αhydroxylase
SKIPPED Miscellaneous examples (3)
•Drugs (e.g. i.v. bisphosphonate therapy in patients with
vitamin D insufficiency/deficiency)
•Osteoblastic metastases
•Acute pancreatitis
Hypoparathyroidism(undersecretion of PTH) is relatively
rare (<200,000 cases in USA)
Hypocalcemia with serum PTH inappropriately low for
hypocalcemic state
Most common cause of hypoparathyroidism
autoimmune destruction of parathyroids/loss of parathyroids due to thyroidectomy
Loss of PTH producing tissue results in
hypocalcemia due to
decreased Ca2+ uptake in gut/kidney, decreased Ca2+
release from bone
Di George Syndrome –
congenital disease with complete lack of
parathyroids at birth
Hypoparathyroidism Treatment: no approved — replacement therapy
hormonal
Conventional treatment of hypoparathyroidism– mainly
calcium and calcitriol [1,25 (OH)2D3] supplementation (but can increase risk of kidney stones due to hypercalciuria)
(2) have been in clinical trials - PTH
1-84 now approved in USA/Europe as adjunctive
treatment for patients not well controlled with
conventional therapy
PTH 1-34 and PTH 1-84
Hypoparathyroidism Associated with
Activating CaSR Mutations
Autosomal dominant hypocalcemia - ADH
Constitutively activating mutations in CaSR cause
autosomal dominant hypocalcemia
CaSR signals constitutively even though Ca2+ levels are
low (i.e.parathyroid “misreads” Ca2+ levels as high and inappropriately suppresses PTH)
Decreases Ca2+ reabsorption in kidney (more excreted in
urine) and decreases release from bone, uptake in gut, etc which leads to
low serum Ca2+
Treatment of Hypoparathyroidism Associated with
Activating CaSR Mutations
mainly calcium and calcitriol [1,25 (OH)2D3]
supplementation but there can be complications of hypercalciuria
(too much calcium in urine) with Ca2+ supplementation
Pseudohypoparathyroidism
Insensitivity to PTH
Pseudohypoparathyroidism is hypocalcemia due to
not due to lack of PTH but due to lack
of responsiveness of target tissues to PTH (hence
“pseudohypoparathyroidism”)
in pseudohypoparathyroidism, serum PTH is high as
parathyroid gland keeps trying to
respond to correct the low serum Ca2+
Pseudohypoparathyroidism is due to mutations in
G proteins important for PTH signaling
esp. Gsalpha
Pseudohypoparathyroidism is —
rare
approx 0.7 per 100,000
More common cause of hypocalcemia than hypoparathyroidism
vitamin D deficiency
Vitamin D Deficiency can be due to (3)
dietary deficiency,
lack of sunlight,
malabsorption of vitamin D
Lack of vitamin D inhibits
Ca2+ and Pi uptake in gut (due to
downregulation of calcium and phosphate transport proteins, Calbindins, TRPV6, NaPi-IIb)
Vitamin D Deficiency in children leads to
rickets
rickets (3)
- Impaired bone mineralization/outward curvature of long bones (bowing)
- Insufficiently mineralized vertebrae/curved spine
- Disorganized growth plate/growth retardation
Vitamin D Deficiency in adults leads to
osteomalacia
osteomalacia
failure of osteoid to fully calcify - soft bones
osteomalacia is due to
low serum calcium and phosphate
Low serum Ca2+ / Pi normally requires what kind of vitamin D deficiency?
long term severe
deficiency of Vit D
characteristic of vitamin D deficient rickets
Metaphyseal cupping (flaring)/”fuzzy growth plate
VDDR type I is also known as
pseudovitamin D deficiency rickets
VDDR type I inheritance
AR
VDDR type I is a defect in
renal 25-OH-vitamin D-1α-hydroxylase
VDDR type I is low
serum Ca, Pi
VDDR type I is high
PTH
VDDR type I is very low
1,25(OH)2D3
VDDR type II is also known as
hereditary vitamin D resistant rickets
VDDR type II inheritance
AR
VDDR type II is a defect in
vitamin D receptor (VDR)
VDDR type II several — identified
mutations
VDDR type II is low
serum Ca, Pi
VDDR type II is high
PTH
VDDR type II: — in some patients
alopecia
VDDR type II is elevated
1,25(OH)2D3
pseudohypoparathyroidism
(lack of responsiveness to PTH)
•Mutation in — gene involved in PTH receptor signaling
GNAS
Hypoparathyroidism (under production of PTH)
•Parathyroid agenesis (Di George syndrome)
•Autoimmune destruction of —
•Loss of parathyroid tissue during — —-
•Activating CaSR mutations which inappropriately
parathyroid
thyroid surgery
suppress PTH secretion
Vitamin D Deficient Rickets is due to
- Dietary/ malabsorption
* Low sunlight
Vitamin D Dependent Rickets
•Type I - Mutation in
•Type II – Mutation in
renal 25-OH- vitamin D-1α-hydroxylase
Vitamin D receptor
Hypercalcemia –
blood calcium concentration higher
than normal range (>1.1-1.35mM ionized)
symptoms of hypercalcemia (7)
- Fatigue
- Electrocardiogram abnormalities
- Nausea, vomiting, constipation
- Anorexia
- Abdominal pain
- Hypercalciuria/kidney stone formation
- Calcification of soft tissues – (e.g. vasculature).
Hypercalcemic crisis occurs at — ionized serum
calcium
> 2.5mM (emergency situation – can lead to, anuria/oliguria,
coma, somnolence)
causes of hypercalcemia (3)
elevated PTH levels
elevated 1,25(OH)2D3 levels
miscellaneous
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cause of elevated PTH levels in hypercalcemia (5
- Primary Hyperparathyroidism
- Familial hyperparathyroidism (MEN, FHH, HPT-JT)
- Inactivating mutations of CaSR
- Secondary to hypophosphatemia
- Secondary to parathyroid tumors
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causes of Elevated 1,25(OH)2D3 levels in hypercalcemia (1)
Hypervitaminosis D (vitamin D intoxication)
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miscellaneous causes of hypercalcemia (2)
•Hypercalcemia of malignancy – due to tumor production of
factors which stimulate bone resorption (e.g. PTHrP)
•Severe dehydration – will increase serum Ca2+ concentration
without changing total blood calcium
Primary Hyperparathyroidism (PHPT) is a relatively common
endocrine disorder of parathyroid
hyperfunction (PTH oversecretion) (1 in 500 – 1 in 1000)
Usually, 1 of 4 parathyroid glands makes too much PTH
due to
development of benign adenoma resulting in
excessive PTH synthesis/secretion (85% of cases)
Hypercalcemia
PTH hypersecretion not adequately
inhibited by normal negative feedback response to
elevated Ca2+
in Primary Hyperparathyroidism (PHPT),
•Phosphate usually —
•High — —-
•Kidney stones due to
low (decreased renal reabsorption)
bone turnover (increased resorption and formation)
hypercalciuria
treatment of Primary Hyperparathyroidism (PHPT)
parathyroidectomy
MEN1 (2)
•Due to inactivation of tumor suppressor gene Menin (gene
name MEN, One copy of gene is mutated, but “second hit”
needed for tumor formation
•Rare: 2-3 per 100,000 (accounts for ~2% of 1o HPT cases)
MEN2A (3)
- Due to gain of function mutation in RET protooncogene
- AD inheritance
- Generally milder than MEN1
Mutations in MEN result in
neoplastic tumors in several endocrine tissues (and other tissues), including parathyroids – i.e. more PTH secretion
Heterozygotes for inactive CaSR have
familial
hypocalciuric hypercalcemia
in familial primary hyperthyroidism, CaSR doesn’t signal even though
Ca2+ levels are high (i.e.
parathyroid misreads Ca2+ levels as being low) therefore
PTH is inappropriately elevated
familial primary hyperthyroidism results in
elevated serum Ca2+ and lower than normal Pi
Familial Primary Hyperparathyroidism is largely
asymptomatic
Familial Primary Hyperparathyroidism homozygotes have
neonatal severe hyperparathyroidism
NSHPT
neonatal severe hyperparathyroidism
(NSHPT) is potentially
fatal - requires parathyroidectomy
Hypercalcemia can occur due to
tumors secreting factors that
stimulate bone resorption (e.g.
breast cancer, myeloma)
Some cancers, e.g. (2)
secrete PTHrP - mimics PTH
actions
squamous
carcinomas, some breast cancers,
Causes severe problems due to (2)
bone degradation and elevated
serum calcium
Hypercalcemia of Malignancy can be
life threatening
Secondary Hyperparathyroidism
Oversecretion of PTH in response to conditions of
hypocalcemia and/or decreased 1,25(OH)2D3
most common cause of Secondary Hyperparathyroidism
chronic renal failure
why is chronic renal failure the most common cause of secondary hyperparathyroidism
ailing kidneys can’t produce much 1,25(OH)2D3, which normally inhibits PTH, and do not excrete Pi adequately, resulting in insoluble calcium phosphate forming and removal of Ca2+ from circulation
Secondary Hyperparathyroidism can also be caused by
vit D malabsorption
Secondary Hyperparathyroidism treatment
aimed at correctly the underlying cause of the hypocalcemia
Secondary Hyperparathyroidism is usually improved in patients who undergo
kidney transplant
In patients with chronic renal failure- (4)
dietary P restriction,
VitD supplements,
phosphate binders,
calcimimetics (stimulate CaSR)
Hypophosphatemia
Phosphate levels lower than normal range (<0.8-1.5mM)
<2.5-4.5mg/dL
Hypophosphatemia is relatively common- occurs in
5% of hospitalized
patients (increases to 30% in alcoholics and patients w/
severe sepsis)
causes of Hypophosphatemia (3)
Decreased intestinal absorption of phosphate
Increased urinary excretion
Redistribution from extracellular fluid into cells/tissues
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Decreased intestinal absorption of phosphate (5)
•Dietary Vitamin D deficiency/low sun exposure
•Vitamin D receptor defects/synthetic defects
•Malabsorption of vitamin D (Celiac Disease, Crohn’s disease,
bowel resection, gastric bypass, chronic diarrhea, etc.)
•Nutritional deficiencies (alcoholism, anorexia, starvation)
•Antacids containing aluminum/magnesium
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Decreased intestinal absorption of phosphate (4)
- Renal phosphate wasting disorders
- Primary and secondary hyperparathyroidism (i.e. increased PTH)
- Mutations in FGF23 (PHEX or Dmp1)
- Mutations in NaPi-IIc (sodium/phosphate cotransporter gene)
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Increased urinary excretion
Redistribution from extracellular fluid into cells/tissues (3)
•Hungry bone syndrome (increased demand for calcium and
phosphate for bone formation after parathyroidectomy)
•Refeeding syndrome (after starvation)
•Treatment of diabetic ketoacidosis
Rickets/Osteomalacia are Diseases
Associated with
Hypophosphatemia
X-linked Hypophosphatemic
Rickets (XLH) is the most common disorder of
renal phosphate wasting, (3.9–5
per 100,000 live births)
features of XLH (4)
growth retardation, rachitic/ osteomalacic bone
disease, dental abscesses, weak bones (fractures)
XLH is due to
mutations in PHEX gene on X-chromosome (phosphate-
regulating gene with homologies to endopeptidases on the X chromosome)
XLH inheritance pattern
x linked dominant
how many mutations described of XLH?
> 400
PHEX produced by (3)
osteoblasts, osteocytes, odontoblasts
PHEX normally inhibits
FGF23 production
XLH mutations of PHEX lead to
inappropriately elevated
FGF23 production, even though serum phosphate is low
(mainly by osteocytes)
FGF23 reduces
renal reabsorption of phosphate (leads to
renal phosphate wasting - i.e. more excreted in urine)
XLH results in
- — serum Pi
- — (2ry to reduced renal phosphate reabsorption)
- — 1,25(OH)2D3 (should be elevated with low serum Pi, but inhibited by FGF23)
low
phosphaturia
low
XLH Treatment (2)
Phosphate supplementation
high dose calcitriol
XLH treatment response to treatment depends on
age of patient at time of initiation
XLH may require surgical intervention to correct
limb deformities
Treatment of XLH can be reduced to
lower doses of phosphate and/or calcitriol or no medications in some adults
Clinical trials started using — — as a new
therapy for XLH
FGF23 antibodies
ADHR: (2)
•Rare form of inherited hypophosphatemic rickets- symptoms
similar to XLH
•Due to mutations in FGF23 that alter cleavage site so it
cannot be proteolytically inactivated – FGF23 stays active
longer
ARHR: (4)
•Recessively inherited hypophosphatemic rickets - symptoms
similar to XLH
•Due to mutations in Dmp1
•Dmp1 expressed by osteocytes and negatively regulates
FGF23
•Mutation in Dmp1 leads to overproduction of FGF23
HHRH
Hereditary Hypophosphatemic Rickets with Hypercalciuria
HHRH is a rare inherited form of
hypophosphatemic rickets
HHRH due to
heterozygous or homozygous loss of function
mutations in type II sodium phosphate cotransporter
NaPiIIc (gene name SLC34A3
HHRH is clinically similar to
XLH but with elevated levels of 1,25
(OH)2D3
treatment of HHRH
phosphate supplements alone (not calcitriol)
XHL, ADHR, and ARHR1 lead to increased
FGF23
HHRH is due to reduced function of
Na+ dependent phosphate transporter which is a
target gene of FGF23
Tumor Induced Osteomalacia (TIO) is an acquired syndrome of
renal phosphate wasting
Factors secreted into circulation by tumors
cause alterations in Pi metabolism that
mimic
hyophosphatemic rickets
Serum biochemistry of TIO is the same as for
hypophosphatemic rickets
Children with TIO display
rickets-like
features
FGF23 levels go down with
surgical
resection of tumor – may require
supplementation with phosphate and
calcitriol
Symptoms of acute (short term) hyperphosphatemia: (2)
•Hypocalcemia (muscle tetany, etc.) (due to calcium precipitating with phosphate in soft tissues, reducing serum calcium)
•Suppresses 1 α-hydroxylase activity in kidney, lowering
1,25D3 levels, which further exacerbates hypocalcemia by
reducing Ca2+ uptake in gut/renal reabsorption
Chronic hyperphosphatemia symptoms: (2)
•Soft tissue (incl. vasculature) calcification, renal failure, 2ry
hyperparathyroidism, renal osteodystrophy.
•Hyperphosphatemia from renal failure plays a key role in
development of secondary hyperparathyroidism
Symptoms of hyperphosphatemia mainly related to
knock-on effects on calcium homeostasis
causes of hyperphosphatemia (4)
Acute Phosphate load (increased intestinal uptake)
Decreased urinary excretion
Redistribution to extracellular space
Genetic causes of hyperphosphatemia (Familial Tumoral calcinosis)
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Acute Phosphate load (increased intestinal uptake) (2)
- Phosphate containing laxatives/enemas
* Rapid administration of phosphate (oral, I.V. rectal)
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Decreased urinary excretion (3)
- Renal insufficiency/failure
- Secondary to hypoparathyroidism /pseudohypoparathyroidism
- Vitamin D intoxication
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Redistribution to extracellular space (2)
- Metabolic/respiratory acidosis/diabetic ketoacidosis
* Severe systemic infections
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Genetic causes of hyperphosphatemia (Familial Tumoral calcinosis) (3)
- Inactivating mutations in FGF23
- Inactivating mutations of Klotho (FGF23 receptor)
- Others
Treatment of hyperphosphatemia involves administration of
phosphate binding salts – calcium, magnesium, aluminum. Aluminum avoided in patients with renal failure
Dentists should understand how disorders of Ca2+ / Pi
metabolism
impact the patient (e.g. short stature, weak,
undermineralized skeleton, defects in alveolar bone)
Increased incidence of periodontitis/periapical abcesses
suggested in patients with
hypophosphatemic
rickets/osteomalacia
Some patients with Vit D-dependent rickets have dental
abnormalities - such as
thin enamel, hypomineralization→
microscopic cracks harbor bacteria → frequent cavities.
Patients with hypercalcemia of malignancy often treated
with
high dose bisphosphonates – risk of developing BONJ
what are commonly seen with hyperphosphatemia?
Poor muscle tone (hypotonia)/ muscle weakness are
common/ seizures can occur
