Chapter 6 - Disorders of calcium Flashcards
T/F: Increased serum iCa inhibit PTH
T
How does increased iCa lead to decreased PTH secretion (behind the rapid and slow mechanisms)?
The initial effect to decrease PTH secretion is rapid (occurring within 2 to 3 minutes), mediated by the calcium receptor with a cascade of resulting intracellular events and involving mediation by arachidonate. Slower effects are caused by inhibition of synthesis of PTH mRNA and its translation to hormone.
Does calcitriol inhibit or stimulate PTH synthesis?
Calcitriol is an important inhibitor of PTH synthesis
How does calcitriol inhibit PTH synthesis? (long and short negative feedback)
- The short negative feedback loop is mediated by the binding of calcitriol to the calcitriol receptor in parathyroid cells, with inhibition of transcription of the PTH gene
- The long negative feedback loop is completed when an increased serum iCa concentration (that will inhibit PTH secretion) results from PTH stimulation of renal calcitriol production and subsequent enhanced gastrointestinal absorption of calcium
What is the half-life of PTH?
3 to 5 minutes
How is PTH destroyed by the body?
PTH is removed by fixed macrophages. The kidneys and bone also participate in destruction of intact PTH.
Cite the 4 most important biologic effects of PTH on calcium
(1) increase the blood calcium concentration
(2) increase tubular reabsorption of calcium, resulting in decreased calcium loss in the urine
(3) increase bone resorption and the numbers of osteoclasts on bone surfaces
(4) accelerate the formation of the principal active vitamin D metabolite
What is the biphasic response of bone to PTH?
- The immediate effects are the result of increasing the activity of existing bone cells. This results in an increased flow of calcium from deep in bone to bone surface through the action of an osteocyte-osteoblast “pump”.
- The later effects of PTH on bone are potentially of greater magnitude and are not dependent on the continuous presence of hormone. Osteoclasts are primarily responsible for the long-term action of PTH on increasing bone resorption and overall bone remodeling.
T/F: PTH-like factor is only related to the pathogenesis of humoral hypercalcemia of malignancy
F, it has numerous actions in the developing fetus and adult animal
What are the pleiotropic actions of vitamin D?
Among others:
- Important roles as antiproli- ferative and prodifferentiative mediators working in part via control of DNA replication
- Roles as immunomodulators, including effects on glomerulonephritis and encephalitis.
- Role of calcitriol (Vit D2) to regulate expression of the insulin receptor
What is the generic term for all bioactive metabolites of Vitamin D2?
Calcitriol
What is the generic term for all bioactive metabolites of Vitamin D3?
1,25-dihydroxyvitamin D
What are the principal regulators for renal calcitriol synthesis?
Serum PTH, calcitriol, phosphorus, and calcium concentrations
T/F: a low calcitriol concentration leads to increased PTH concentrations
T,
And increased PTH stimulates the synthesis of calcitriol by the kidneys
T/F: Estrogens and testoterone decrease calcitriol synthesis
F
T/F: Phosphate loading decreases calcitriol synthesis
T
What does calcitriol do to serum calcium and phosphate concentrations?
What is the main target organ?
Calcitriol increases serum calcium and phosphorus concentrations, and its major target organ for these effects is the intestine (others: bone and kidneys)
None fasted animals might have a mild increase OR decrease in serum Ca?
Increase
Two most common causes of hyperCa in dogs?
Malignancy and Addisons disease
An increase in tCa OR iCa is related to the severity of the azotemia?
Total calcium (tCa)
Low dose of calcitriol will help or worsen hyperCa due to CKD?
Help (it gives negative feedback on PTH and thereby reduced Ca. Due to the low dose it does not increase intestinal Ca absorption).
What are the three mechanisms for neoplasia to cause hyperCa?
- Humoral hypercalcemia of malignancy
- Metastasis to bones
- Hematologic malignancy growing in bones
What are the most common forms of neoplasia causing humoral hypercalcemia of malignancy in dogs?
Lymphoma, AGASACA
What are the most common forms of neoplasia causing humoral hypercalcemia of malignancy in cats?
Lymphoma and squamous cell carcinoma
How does PTHrP cause hypercalcemia in dogs with lymphoma?
Stimulate osteoclasts who break down bones and increase serum Ca.
T/F Perianal adenocarcinomas are associated with hypercalcemia
False. But apocrine Gland Anal Sac Adenocarcinoma (AGASACA)
T/F Primary hyperparathyroidism is more common in cats than in dogs
F, it is uncommon in dogs and even less common in cats
What is the most common cause for primary hyperparathyroidism in dogs?
Primary yperparathyroidism was caused by a solitary parathyroid gland adenoma in approximately 90% of dogs, whereas parathyroid gland carcinoma and parathyroid gland hyperplasia each accounted for 5% of cases in one large series
T/F: Parathyroid gland masses usually can be palpated in cats
T: 50% of cats with primary hyperparathyroidism have a palpable cervical mass (usually not palpable in dogs)
What is the most common clinical sign in dogs with primary hyperparathyroidism?
The most common clinical signs were related to urinary tract infections (29%) or urolithiasis (31%).
79% are asymptomatic.
What are the laboratory findings in patients with primary yperparathyroidism?
Increased serum tCa concentration,increased concentration of immunoreactive PTH, increased serum iCa concentration, increased serum ALP, low serum phosphorus concentration, increased or normal calcitriol concentration, undetectable PTHrP
What is the success rate of parathyroidectomy in dogs with primary hyperparathyroidism for the control of hypercalcemia?
94%, within 1 to 6 days
What are alternate ways to surgical ablation for the treatment of primary hyperparathyroidism?
- Ultrasound-guided chemical ablation with ethanol (success rate 72%)
- Ultrasonographically guided radiofrequency heat
ablation of parathyroid masses (success rate 90%)
By which mechanism does hypervitaminosis D lead to hypercalcemia?
Hypervitaminosis D exert hypercalcemic effects, because 25-hydroxyvitamin D competes with calcitriol for binding to the VDR in target tissues. Hypercalcemia results from increased intestinal absorption of calcium, but increased osteoclastic bone resorption and calcium reabsorption from renal distal tubules may also contribute.
What are possible causes for hypervitaminosis D?
- Excessive dietary supplementation (accurate dosing difficult to achieve)
- Ingestion of toxic plants containing glycosides of calcitriol
- Intoxication with cholecalciferol containing rodenticides
- Topical ointments containing potent vitamin D
analogues (calcipotriene) for treatment of human psoriasis - Fun fact: All commercial cat foods provide vitamin D in excess of the minimal requirements
What is the mechanism behind hypercalcemia in dogs with granulomatous disease?
Hypercalcemia can result from calcitriol synthesis by activated macrophages during granulomatous inflammation. Normal macrophages express 1a-hydroxylase activity (which converts 25-hydroxyvitamin D to calcitriol) when stimulated by interferon or lipopolysaccharide.
Give examples of granulomatous disease
Blastomycosis, gastric pythiosis, disseminated histoplasmosis, coccidioidomycosis, schistosomiasis, nocardia and atypical mycobacteria infection, cryptococcosis, actinomyces
What is the most common cause of hypercalcemia in cats?
Idiopathic hypercalcemia of cats (IHC), for months to more than 1 year
What is the serum iCa, PTH and PTHrP concentration in cats with idiopathic hypercalcemia
Serum iCa concentration is increased; PTH concentration is in the lower half of the reference range; and PTHrP is negative
What percentage of cats with calcium oxalate urinary stones have hypercalcemia
As many as 35% of cats with calcium oxalate urinary stones have hypercalcemia
What is the treatment for cats with idiopathic hypercalcemia?
Specific treatment for IHC is impossible because the pathogenesis remains unknown
Why would an AKI patient recovering renal function become hypercalcemic?
Sudden improvement in renal function also may result in a rapid decrease of serum phosphorus concentration, changing mass law interactions between phosphorus and calcium and resulting in transient hypercalcemia
T/F: AKI secondary to grape/raisin ingestion may be associated with hyperphosphatemia and hypercalcemia
T: in up to 93% of the dogs
T/F: Acidosis can magnify the effects of hypercalcemia
T: Acidosis can magnify the effects of hypercalcemia at all serum calcium concentrations by shifting more calcium to the ionized fraction.
T/F: soft tissue mineralization is potentiated by hyperphosphatemia
T
What are the mechanisms behind supportive care for the treatment of hypercalcemia?
Supportive treatments reduce the magnitude of hypercalcemia by:
- Increasing renal calcium excretion
- Inhibiting bone resorption
- Promoting soft tissue deposition of calcium
- Causing a shift of intravascular calcium to other body compartments
- Promoting extrarenal calcium loss
- Reducing calcium transport across the gut
What are the initial / secondary / tertiary considerations for supportive treatment of hypercalcemia?
Initial considerations:
- Fluids (0.9% sodium chloride)
- Furosemide
- Calcitonin
Secondary considerations:
- Glucorticosteroids
- Bisphosphonates
Tertiary considerations:
- Sodium bicarbonate
- Mithramycin (severe toxicity)
- Ethylenediamine tetra-acetic acid (EDTA) (severe toxicity)
- Dialysis
Can you go over the 2 mnemonic ways to remember the differentials for hypercalcemia?
HARD IONS
GOSH DARN IT
HARD IONS
H—Hyperparathyroidism, Humoral hypercalcemia of malignancy, Houseplants
A—Addison’s disease; Aluminum or vitamin A toxicity
R—Renal disease, Raisins (Grapes)
D—Vitamin D toxicosis
I—Idiopathic (particularly in cats; very rare in dogs)
O—Osteolytic
N—Neoplasia (humoral hypercalcemia of malignancy)
S—Spurious
GOSH DARN IT
G—Granulomatous disease, Grapes
O—Osteolytic
S—Spurious
H—Hyperparathyroidism, Humoral hypercalcemia of malignancy, House plants
D—Vitamin D toxicity, Dehydration
A—Addison’s, Vitamin A, or Aluminum toxicity
R—Renal disease
N—Neoplasia (humoral hypercalcemia of malignancy)
I—Idiopathic
T—Temperature (hypothermia)
How does acidemia affect Ca?
Acidemia shifts the calcium concentration so that you get more ionized calcium
What is the recommended fluid choice if hyperCa?
NaCL 0.9%
Why is NaCl the fluid of choice in hypercalcemia?
- Has less Ca than other fluids
* The Na compete for reabsorption with Ca in the renal tubule = increased calciuresis.
T/F: low serum iCa increases excitatibility of neuromuscular tissue
T
What are other electrolytes and acid-base abnormalities that can magnify or diminish the signs of hypocalcemia?
- Correction of hypokalemia in cats with concurrent hypocalcemia
- Alkalosis and subsequent decreases in iCa concentration (respiratory alkalosis, infusion of alkali)
- Depletion or excess of Mg
What are the clinical signs associated with hypocalcemia?
— Common
- None Muscle tremors or fasciculations Facial rubbing (paresthesia?) Muscle cramping Stiff gait Behavioral change Restlessness or excitation Aggression
Hypersensitivity to stimuli Disorientation
— Occasional
Panting Pyrexia Lethargy Anorexia PUPD Prolapse of the third eyelid (cats) Posterior lenticular cataracts Tachycardia or electrocardiographic alterations (prolonged QT–interval)
— Uncommon
Polyuria or polydipsia Hypotension Respiratory arrest or death
What is the most common cause for low tCa?
Hypoalbuminemia
What are the mechanisms (2) behind the hypocalcemia seen in patients with renal failure?
- Decreased synthesis of calcitriol
- Mass law interactions of calcium with markedly increased serum phosphorus concentration
What are the most common conditions associated with hypocalcemia?
Hypoalbuminemia, chronic renal failure, eclampsia, acute renal failure, acute pancreatitis, undefined cause
What are occasional conditions associated with hypocalcemia?
Soft tissue trauma and rhabdomyolysis, hypoparathyroidism (idiopathic, secondary to bilateral thyroidectomy, after sudden reversal of chronic hypercalcemia, secondary to Mg depletion or excess), ethylene glycol intoxication, phosphate enema, after NaHCO3 administration
What is the percentage of dogs with CKD and concomitant low serum iCa concentrations?
40%
What are the critical illnesses that may cause hypocalcemia?
Sepsis, systemic inflammatory response syndrome, hypomagnesemia, AIRF, massive blood transfusion, CPR, acute pancreatitis
T/F: Hypocalcemia in critically ill patients is associated with decreased survival rate
F: Hypocalcemia was associated with longer intensive care unit and hospital stays, but was not associated with decreased survival
What are the suggested mechanisms behind low iCa in acute pancreatitis?
Sequestration of calcium into peripancreatic fat (saponification), increased free fatty acids, increased calcitonin secondary to hyperglucagonemia, and PTH resistance or deficit resulting from the effects of hypomagnesemia
What is the percentage of dogs with DM / DKA that will have ionized hypocalcemia?
47% / 52%
Describe treatment for hypoparathyroidism
Vitamin D metabolites are used to correct the low intestinal absorption of calcium.
Enrofloxacin 5mg/kg IM Q24 x14 days can cause an (increase/decrease) in iCa levels?
Decrease (nadir on day 3 and remained below normal until day 10, however levels normalize after day 14)
How do phosphate enema’s cause hypocalcemia?
Rapid absoprtion of phosphate leads to hyperphosphatemia and subsequent mass low interaction with serum calcium.
What is the most common cause of hypoparathyroidism in dogs? In cats?
Idiopathic in dogs, surgical removal during thyroidectomy in cats
In dogs with primary hypoparathyroidism, the serum total ca is typically less that what level?
less than 6.5mg/dL
What clinical signs may we see with a total calcium level less than 6mg/dL?
Seizures, tetany
How do you obtained a definitive diagnosis of primart hypoparathyroidism?
Combination of clinical signs, low iCa, and PTH concentration inappropriately low to the magnitude of ionized hypocalcemia.
Hypoparathyroidism is the only possible diagnosis when what four factors are occuring together?
1) low serum calcium concentration 2) high serum phosphorus concentration, 3) normal renal function and 4) low PTH concentration
Is PTH decreased or elevated in the following conditions:
Nutritional and renal secondary hyperparathyroidism, after phosphate containting enemas and during tumor lysis syndrome
increased
List and describe the three catergories of causes of hypoparathyroidism
1) Suppressed secretion of PTH without parathyroid gland desctruction
2) Sudden correction of chronic hypercalcemia and
3) absence of desctruction of the parathyroid glands
In what percentage of cats do we see postoperative hypocalcemia in cats following thyroidectomy
20-30%
How many parathyroid glands are required for normocalcemia to be maintained
one functional pt gland
What percentage of dogs post surgical removal of a parathyroid gland tumor can expect to develop clinical signs of hypocalcemia within 3-6 days post-op
50%
Describe how magnesium affects PTH (increase vs decrease etc)
Mild acute hypomagnesemia stimulates PTH, but severe hypomagnesemia decreases PTH
What can canine distemper virus cause in regards to the parathyroid?
CDV induce parathyroid hypofunction can contribute to the development of hypocalcemia
Name a common toxin that can cause hypocalcemia, describe the MOA
ethylene glycol - chelates calcium and becomes deposited in soft tissues
Describe treatment for hypoparathyroidism
Vitamin D metabolites are used to correct the low intestinal absorption of calcium.
What are the risk factors for ionized hypocalcemia in cats with urethral obstruction?
Hyperkalemia and metabolic acidosis (after correction)
T/F: PLE can be associated with severe hypocalcemia
T
Dr. Her adds sodium phosphorous to his fluid to increase the Na content and thereby increase the calciuresis. Is this good or bad for Dr. Hers patient?
Bad. The phosphorous will increase the risk for tissue mineralization.
Dr. Gautier is teaching Henriksson how to manage a patient with hypercalcemia. After rehydration she says that the patient should be given furosemide and IV fluids. Henriksson have been taught in vet school not to administer diuretics and IV fluid at the same time and does not agree with Dr. Gautier. Who is right?
Dr. Gautier is right, Henriksson is wrong, Im sorry, I love you.
Dr. Arnold is debating what diuretic to use for her hypercalcemic patient. Is there a preference between thiazides or furosemide?
Yes. Furosemide is the diuretic of choice. Thiazides are contraindicated since they can cause hypocalcuria.
Dr. Lowe is treating her hypercalcemic patient with sodium bicarbonate. For how long can she expect the effect to last?
120-180min dependent on the given dose.
Dr. Henriksson has a patient with vitamin D toxicity. She wants to treat her patient with prednisone. Dr. Her tells her that steroids can help with hypercalcemia but only if it is due to neoplasia or addisons disease. Who is right?
Henriksson
Calcitonin can be useful and should be considered instead of steroid if a definitive diagnosis has not been made. Name a few disadvantages with calcitonin treatment for hypercalcemia
- expensive
- short lived effect (hours)
- magnitude of effect is unpredictable
- development of resistance to the effect
Dose of calcium recommended to give to patients with tetany or seizures secondary to hypocalcemia
5-15mg/kg (0.5-1.5mL/kg f 10% calcium gluconate)
What type of diet imbalance can cause hypocalcemia?
Excess of phophorus compared to calcium, feeding of BARF
Monitoring recommended while giving IV calcium
HR and ECG
Is hypo- or hyper-adrenocorticism associated with secondary hyperparathyroidism?
HYPERadrenocorticism (92% of dogs have increased concentration of serum PTH)
Adverse events noted with too rapid of infusion of Ca
bradycardia due to cardiotoxicity arising from excessive infusion of ca
ECG changes that may be seen as IV Cagluc is given
Sudden elevation of the ST segment or shortening of the QT interval
T/F: Measurement of biologically active PTHrp in the dog can be done with tests for human PTHrp (two site IRMA and N terminal RIA).
True- there is a high degree of sequence homology between the species.
T/F: PTH circulates as predominantly intact PTH and carboxyl fragments, which is biologically active.
True
What special handling should be done with samples when testing for Vitamin D metabolites?
Samples should not be exposed to light
How does increased serum iCa decrease cellular function?
It causes alterations in the cell membrane permeability and cell membrane Ca pump activity.
What are some common clinical signs of hyperCa?
PD, PU, anorexia, lethargy and weakness; dehydration, vomiting, pre-renal azotemia, CRF
In a patient with hyperCa, what is the most important bloodwork finding that determines the extent of soft tissue mineralization?
Serum P concentration at the time hyperCa develops
What is the equation for determining severity of soft tissue mineralization with hyperCa?
Ca x P >60
T/F: Soft tissue mineralization occurs regardless of serum P concentration in severe hyperCa.
True
Name some causes of azotemia caused by hyperCa (5)
a. Prerenal reduction in ECF (dehydration from vomiting and PU)
b. Renal vasoconstriction
c. Decreased permeability coefficient of the glomerulus
d. Acute tubular necrosis from ischemia and toxic effects
e. CRF (from nephron loss, nephrocalcinosis, tubulointerstitial inflammation and interstitial fibrosis)
T/F: In dogs, decreased urinary concentrating ability and polyuria are early functional effects of hyperCa.
True
T/F: In cats with hyperCa, urinary concentration may be well preserved.
True, if they do not have CRF
Why is there a decreased urinary concentrating ability with hyperCa?
Reduced tubular reabsorption of Na and impaired action of ADH on tubular cells in the collecting duct
A 10 year old FS DSH presents to you for vomiting and polyuria of 2 days. PE shows a severe dehydration (8-10%). BW showed hyperCa (confirmed with iCa) and azotemia. U/A showed isothenuria. Is this patient in renal failure?
Not necessarily, owing to the hyperCa, if early, the urinary concentrating effect can occur without structural renal lesions and the patient is severely dehydrated.
The toxic effects of hyperCa are increased in patients with CRF- Why?
Increased PTH concentrations which cause increased Ca entry into cells.
What places in the nephron show the earliest structural lesions with hyperCa?
Ascending loop of Henle and the distal convoluted tubule
Hypercalcemia of malignancy is present in what percentage of canine cases with hyperCa?
1/3 to more than 1/2
T/F: The importance of calcitriol in tissue is proportional to the abundance of the VDR in the cells.
True
What causes the transport of calcium and phosphate from the intestinal lumen to the plasma across the enterocyte?
Calcitriol
Calcitriol increases brush border permeability to calcium and induces the synthesis of what?
Calbindin-D 9k
These serve as buffers to protect enterocytes from toxic concentrations of Ca++ while ferrying Ca across the cell.
Calbindins
This stimulates rapid Ca transport across the enterocyte.
Calcitriol
Describe the number of calcitriol receptors and calbindin concentrations from the duodenum to ileum.
Progressive decrease
This deficiency leads to rickets in young/ growing animals.
Vitamin D deficiency
This deficiency can lead to osteomalacia in adults.
Vitamin D deficiency
Name the bone proteins that calcitriol regulates (4)
ALP, collagen Type I, osteocalcin, osteopontin
What enzyme does calcitriol inhibit in the kidneys to help regulate itself?
25-hydroxyvitaminD-1a-hydroxylase
What effect does calcitriol have on the reabsorptioin of Ca and P from the glomerular filtrate?
Increases reabsorption
What effect does calcitriol have on the production of PTH?
Inhibition
How does calcitriol inhibit PTH? (2 ways)
- Binding of calcitriol to the parathyroid chief cells directly inhibits PTH synthesis,
- Calcitriol stimulates intestinal Ca absorption which indirectly decreased PTH secretion by increasing serum iCa concentration
T/F: Suppression of PTH cannot occur in the absence of calcitriol, even in the presence of hyperCa.
True
Where is calcitriol synthesized?
The C cells of the thyroid gland
Name 2 stimuli for calcitonin.
HyperCa and Ca rich meal
What is calcitonin’s role with regards to bone?
Inhibits osteoclastic bone resorption (Calcitonin puts the bone in)
T/F: HyperCa results in decreased PTH secretion, decreased intracellular degradation of PTH in chief cells and decreased PTH synthesis.
False- it increases cellular degradation of PTH in chief cells
T/F: The serum total Ca concentration is directly proportional to iCa.
False
Why should you not use oxalate, citrate or erhylenediaminetratraacetic acid anticoagulants to evaluate calcium?
Ca binds to these chemicals and becomes unavailable for analysis
What is the normal serum total calcium concentration in a normal adult dog?
10mg/dL
What is the normal serum total calcium concentration in a normal cat?
9mg/dL
What is the normal serum total calcium concentration in a puppy less than 3 months of age?
11mg/dL
What percentage of bound calcium is bound to albumin?
80-90%
Name 3 places containing iCa cell membrane receptors that help regulate calcium ions.
Parathyroid chief cells, Thyroid C cells, renal tubular cells
T/F: Ionized Ca concentrations in dogs and cats are typically lower in heparinized whole blood is compared with serum iCa measurement.
True
A 7y MN Golden retriever presented to one of the interns on overnight with a history of lethargy. rDVM BW shows an increased total Ca. The intern was going to run an iCa but the NOVA was broken, so they put an adequately filled heparin tube aside at 2am. It is now 7am and Dr. Henriksson wants to run an iCa. Should she use the blood?
No, the pH of the blood increases over time, causing dissociation of Ca and a false increase in iCa.
