Hormonal Control of Calcium and Phosphate: Part 2 Flashcards
(141 cards)
1
Q
Hypocalcemia
A
low serum calcium
2
Q
Hypercalcemia
A
high serum calcium
3
Q
Hypophosphatemia
A
low serum phosphate
4
Q
Hyperphosphatemia
A
high serum phosphate
5
Q
Calcium and Phosphate Homeostasis can be
Disrupted in Many Different ways: (7)
A
•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
6
Q
Chronic kidney disease affects Ca2+ /Pi homeostasis because
A
impaired kidney function interferes with Ca2+ and Pi reabsorption
7
Q
Hypocalcemia - blood calcium concentration…
A
below normal range (<1.1-1.35 mM ionized calcium)
8
Q
Symptoms of hypocalcemia (depending on rapidity of onset and whether hypocalcemia is mild or severe): (6)
A
- Muscle cramping
- Muscle spasms
- Increased neuromuscular excitability
- Fatigue
- Cardiac dysfunction
- Depression, psychosis, seizures
9
Q
causes of hypocalcemia (6)
A
inadequate PTH production
syndromes with component of hypoparathyroidism
PTH resistance
inadequate vitamin D
vitamin D resistance or synthesis defects
miscellaneous
10
Q
SKIPPED
Inadequate PTH production examples (7)
A
•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
11
Q
SKIPPED
Syndromes with component of hypoparathyroidism examples (5)
A
•DiGeorge syndrome •HDR (hypoparathyroidism, deafness, renal anomalies) syndrome •Kenney-Caffey syndrome •Sanjad-Sakati syndrome •Kearns-Sayre syndrome
12
Q
SKIPPED
Vitamin D resistance or synthesis defects
(Vitamin D dependent Rickets) example (1)
A
•Mutations in VDR or 1αhydroxylase
13
Q
SKIPPED Miscellaneous examples (3)
A
•Drugs (e.g. i.v. bisphosphonate therapy in patients with
vitamin D insufficiency/deficiency)
•Osteoblastic metastases
•Acute pancreatitis
14
Q
Hypoparathyroidism(undersecretion of PTH) is relatively
A
rare (<200,000 cases in USA)
15
Q
Hypocalcemia with serum PTH inappropriately low for
A
hypocalcemic state
16
Q
Most common cause of hypoparathyroidism
A
autoimmune destruction of parathyroids/loss of parathyroids due to thyroidectomy
17
Q
Loss of PTH producing tissue results in
A
hypocalcemia due to
decreased Ca2+ uptake in gut/kidney, decreased Ca2+
release from bone
18
Q
Di George Syndrome –
A
congenital disease with complete lack of
parathyroids at birth
19
Q
Hypoparathyroidism Treatment: no approved — replacement therapy
A
hormonal
20
Q
Conventional treatment of hypoparathyroidism– mainly
A
calcium and calcitriol [1,25 (OH)2D3] supplementation (but can increase risk of kidney stones due to hypercalciuria)
21
Q
(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
A
PTH 1-34 and PTH 1-84
22
Q
Hypoparathyroidism Associated with
Activating CaSR Mutations
A
Autosomal dominant hypocalcemia - ADH
23
Q
Constitutively activating mutations in CaSR cause
A
autosomal dominant hypocalcemia
24
Q
CaSR signals constitutively even though Ca2+ levels are
A
low (i.e.parathyroid “misreads” Ca2+ levels as high and inappropriately suppresses PTH)
25
Decreases Ca2+ reabsorption in kidney (more excreted in
| urine) and decreases release from bone, uptake in gut, etc which leads to
low serum Ca2+
26
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
27
Pseudohypoparathyroidism
Insensitivity to PTH
28
Pseudohypoparathyroidism is hypocalcemia due to
not due to lack of PTH but due to lack
of responsiveness of target tissues to PTH (hence
“pseudohypoparathyroidism”)
29
in pseudohypoparathyroidism, serum PTH is high as
parathyroid gland keeps trying to
| respond to correct the low serum Ca2+
30
Pseudohypoparathyroidism is due to mutations in
G proteins important for PTH signaling
| esp. Gsalpha
31
Pseudohypoparathyroidism is ---
rare
| approx 0.7 per 100,000
32
More common cause of hypocalcemia than hypoparathyroidism
vitamin D deficiency
33
Vitamin D Deficiency can be due to (3)
dietary deficiency,
lack of sunlight,
malabsorption of vitamin D
34
Lack of vitamin D inhibits
Ca2+ and Pi uptake in gut (due to
| downregulation of calcium and phosphate transport proteins, Calbindins, TRPV6, NaPi-IIb)
35
Vitamin D Deficiency in children leads to
rickets
36
rickets (3)
* Impaired bone mineralization/outward curvature of long bones (bowing)
* Insufficiently mineralized vertebrae/curved spine
* Disorganized growth plate/growth retardation
37
Vitamin D Deficiency in adults leads to
osteomalacia
38
osteomalacia
failure of osteoid to fully calcify - soft bones
39
osteomalacia is due to
low serum calcium and phosphate
40
Low serum Ca2+ / Pi normally requires what kind of vitamin D deficiency?
long term severe
| deficiency of Vit D
41
characteristic of vitamin D deficient rickets
Metaphyseal cupping (flaring)/”fuzzy growth plate
42
VDDR type I is also known as
pseudovitamin D deficiency rickets
43
VDDR type I inheritance
AR
44
VDDR type I is a defect in
renal 25-OH-vitamin D-1α-hydroxylase
45
VDDR type I is low
serum Ca, Pi
46
VDDR type I is high
PTH
47
VDDR type I is very low
1,25(OH)2D3
48
VDDR type II is also known as
hereditary vitamin D resistant rickets
49
VDDR type II inheritance
AR
50
VDDR type II is a defect in
vitamin D receptor (VDR)
51
VDDR type II several --- identified
mutations
52
VDDR type II is low
serum Ca, Pi
53
VDDR type II is high
PTH
54
VDDR type II: --- in some patients
alopecia
55
VDDR type II is elevated
1,25(OH)2D3
56
pseudohypoparathyroidism
(lack of responsiveness to PTH)
•Mutation in --- gene involved in PTH receptor signaling
GNAS
57
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
58
Vitamin D Deficient Rickets is due to
* Dietary/ malabsorption
| * Low sunlight
59
Vitamin D Dependent Rickets
•Type I - Mutation in
•Type II – Mutation in
renal 25-OH- vitamin D-1α-hydroxylase
| Vitamin D receptor
60
Hypercalcemia –
blood calcium concentration higher
| than normal range (>1.1-1.35mM ionized)
61
symptoms of hypercalcemia (7)
* Fatigue
* Electrocardiogram abnormalities
* Nausea, vomiting, constipation
* Anorexia
* Abdominal pain
* Hypercalciuria/kidney stone formation
* Calcification of soft tissues – (e.g. vasculature).
62
Hypercalcemic crisis occurs at --- ionized serum
| calcium
>2.5mM (emergency situation – can lead to, anuria/oliguria,
| coma, somnolence)
63
causes of hypercalcemia (3)
elevated PTH levels
elevated 1,25(OH)2D3 levels
miscellaneous
64
SKIPPED
| 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
65
SKIPPED
| causes of Elevated 1,25(OH)2D3 levels in hypercalcemia (1)
Hypervitaminosis D (vitamin D intoxication)
66
SKIPPED
| 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
67
Primary Hyperparathyroidism (PHPT) is a relatively common
endocrine disorder of parathyroid
| hyperfunction (PTH oversecretion) (1 in 500 – 1 in 1000)
68
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)
69
Hypercalcemia
PTH hypersecretion not adequately
inhibited by normal negative feedback response to
elevated Ca2+
70
in Primary Hyperparathyroidism (PHPT),
•Phosphate usually ---
•High --- ----
•Kidney stones due to
low (decreased renal reabsorption)
bone turnover (increased resorption and formation)
hypercalciuria
71
treatment of Primary Hyperparathyroidism (PHPT)
parathyroidectomy
72
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)
73
MEN2A (3)
* Due to gain of function mutation in RET protooncogene
* AD inheritance
* Generally milder than MEN1
74
Mutations in MEN result in
neoplastic tumors in several endocrine tissues (and other tissues), including parathyroids – i.e. more PTH secretion
75
Heterozygotes for inactive CaSR have
familial
| hypocalciuric hypercalcemia
76
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
77
familial primary hyperthyroidism results in
elevated serum Ca2+ and lower than normal Pi
78
Familial Primary Hyperparathyroidism is largely
asymptomatic
79
Familial Primary Hyperparathyroidism homozygotes have
neonatal severe hyperparathyroidism
| NSHPT
80
neonatal severe hyperparathyroidism
| (NSHPT) is potentially
fatal - requires parathyroidectomy
81
Hypercalcemia can occur due to
tumors secreting factors that
stimulate bone resorption (e.g.
breast cancer, myeloma)
82
Some cancers, e.g. (2)
secrete PTHrP - mimics PTH
actions
squamous
| carcinomas, some breast cancers,
83
Causes severe problems due to (2)
bone degradation and elevated
| serum calcium
84
Hypercalcemia of Malignancy can be
life threatening
85
Secondary Hyperparathyroidism
Oversecretion of PTH in response to conditions of
| hypocalcemia and/or decreased 1,25(OH)2D3
86
most common cause of Secondary Hyperparathyroidism
chronic renal failure
87
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
88
Secondary Hyperparathyroidism can also be caused by
vit D malabsorption
89
Secondary Hyperparathyroidism treatment
aimed at correctly the underlying cause of the hypocalcemia
90
Secondary Hyperparathyroidism is usually improved in patients who undergo
kidney transplant
91
In patients with chronic renal failure- (4)
dietary P restriction,
VitD supplements,
phosphate binders,
calcimimetics (stimulate CaSR)
92
Hypophosphatemia
Phosphate levels lower than normal range (<0.8-1.5mM)
| <2.5-4.5mg/dL
93
Hypophosphatemia is relatively common- occurs in
5% of hospitalized
patients (increases to 30% in alcoholics and patients w/
severe sepsis)
94
causes of Hypophosphatemia (3)
Decreased intestinal absorption of phosphate
Increased urinary excretion
Redistribution from extracellular fluid into cells/tissues
95
SKIPPED
| 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
96
SKIPPED
| 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)
97
SKIPPED
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
98
Rickets/Osteomalacia are Diseases
| Associated with
Hypophosphatemia
99
X-linked Hypophosphatemic
| Rickets (XLH) is the most common disorder of
renal phosphate wasting, (3.9–5
| per 100,000 live births)
100
features of XLH (4)
growth retardation, rachitic/ osteomalacic bone
| disease, dental abscesses, weak bones (fractures)
101
XLH is due to
mutations in PHEX gene on X-chromosome (phosphate-
| regulating gene with homologies to endopeptidases on the X chromosome)
102
XLH inheritance pattern
x linked dominant
103
how many mutations described of XLH?
>400
104
PHEX produced by (3)
osteoblasts, osteocytes, odontoblasts
105
PHEX normally inhibits
FGF23 production
106
XLH mutations of PHEX lead to
inappropriately elevated
FGF23 production, even though serum phosphate is low
(mainly by osteocytes)
107
FGF23 reduces
renal reabsorption of phosphate (leads to
| renal phosphate wasting - i.e. more excreted in urine)
108
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
109
XLH Treatment (2)
Phosphate supplementation
| high dose calcitriol
110
XLH treatment response to treatment depends on
age of patient at time of initiation
111
XLH may require surgical intervention to correct
limb deformities
112
Treatment of XLH can be reduced to
lower doses of phosphate and/or calcitriol or no medications in some adults
113
Clinical trials started using --- --- as a new
| therapy for XLH
FGF23 antibodies
114
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
115
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
116
HHRH
Hereditary Hypophosphatemic Rickets with Hypercalciuria
117
HHRH is a rare inherited form of
hypophosphatemic rickets
118
HHRH due to
heterozygous or homozygous loss of function
mutations in type II sodium phosphate cotransporter
NaPiIIc (gene name SLC34A3
119
HHRH is clinically similar to
XLH but with elevated levels of 1,25
| (OH)2D3
120
treatment of HHRH
phosphate supplements alone (not calcitriol)
121
XHL, ADHR, and ARHR1 lead to increased
FGF23
122
HHRH is due to reduced function of
Na+ dependent phosphate transporter which is a
| target gene of FGF23
123
Tumor Induced Osteomalacia (TIO) is an acquired syndrome of
renal phosphate wasting
124
Factors secreted into circulation by tumors
cause alterations in Pi metabolism that
mimic
hyophosphatemic rickets
125
Serum biochemistry of TIO is the same as for
hypophosphatemic rickets
126
Children with TIO display
rickets-like
| features
127
FGF23 levels go down with
surgical
resection of tumor – may require
supplementation with phosphate and
calcitriol
128
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
129
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
130
Symptoms of hyperphosphatemia mainly related to
knock-on effects on calcium homeostasis
131
causes of hyperphosphatemia (4)
Acute Phosphate load (increased intestinal uptake)
Decreased urinary excretion
Redistribution to extracellular space
Genetic causes of hyperphosphatemia (Familial Tumoral calcinosis)
132
SKIPPED
| Acute Phosphate load (increased intestinal uptake) (2)
* Phosphate containing laxatives/enemas
| * Rapid administration of phosphate (oral, I.V. rectal)
133
SKIPPED
| Decreased urinary excretion (3)
* Renal insufficiency/failure
* Secondary to hypoparathyroidism /pseudohypoparathyroidism
* Vitamin D intoxication
134
SKIPPED
| Redistribution to extracellular space (2)
* Metabolic/respiratory acidosis/diabetic ketoacidosis
| * Severe systemic infections
135
SKIPPED
| Genetic causes of hyperphosphatemia (Familial Tumoral calcinosis) (3)
* Inactivating mutations in FGF23
* Inactivating mutations of Klotho (FGF23 receptor)
* Others
136
Treatment of hyperphosphatemia involves administration of
phosphate binding salts – calcium, magnesium, aluminum. Aluminum avoided in patients with renal failure
137
Dentists should understand how disorders of Ca2+ / Pi
| metabolism
impact the patient (e.g. short stature, weak,
| undermineralized skeleton, defects in alveolar bone)
138
Increased incidence of periodontitis/periapical abcesses
| suggested in patients with
hypophosphatemic
| rickets/osteomalacia
139
Some patients with Vit D-dependent rickets have dental
| abnormalities - such as
thin enamel, hypomineralization→
| microscopic cracks harbor bacteria → frequent cavities.
140
Patients with hypercalcemia of malignancy often treated
| with
high dose bisphosphonates – risk of developing BONJ
141
what are commonly seen with hyperphosphatemia?
Poor muscle tone (hypotonia)/ muscle weakness are
| common/ seizures can occur
