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Pathophysiology - Endocrine and Reproductive > Calcium Homeostasis and Disorders of Calcium Metabolism > Flashcards

Calcium Homeostasis and Disorders of Calcium Metabolism Flashcards

1
Q

What pharyngeal pouch is the thymus derived from? What else is derived from the same pouch?

A

3rd pharyngeal pouch

Vental: Thymus
Dorsal: Lower parathyroids

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2
Q

What are three inhibitors of PTH?

A
  1. Calcitriol (think of this as negative feedback)
  2. Hypomagnesia - important because hypomagnesia is a cause of hypocalcemia, and can be treated with Mg+2 supplements
  3. Hypercalcemia - via calcium sensing receptor
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3
Q

What causes familial hypocalciuric hypercalcemia? What is it characterized by clinically?

A

Autosomal dominant disorder caused by defect calcium sensing receptor -> higher calcium levels required to suppress PTH release. Gq receptor which is activated to block PTH release.

Causes hypocalciuria and mild hypercalcemia with elevated PTH levels. Usually asymptomatic.

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4
Q

What does an activating mutation of the CaSR cause?

A

Familial hypercalciuric hypocalcemia (opposite of other)

  • > PTH is suppressed at lower calcium levels
  • > also called hypoparathyroidism with hypercalciuria
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5
Q

How much sun exposure is required to make adequate amounts of vitamin D3?

A

10-15 minutes of sun exposure at least 2x per weeks on a major body area
-> very little is needed

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6
Q

What happens to 25-hydroxy-D3 in the absence of PTH? What is the test of choice for testing for vitamin D deficiency?

A

It is converted to inactive 24,25-hydroxy-D3

Testing for 25-OH-D3 (calcidiol) is the test of choice

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7
Q

What is the net effect of calcitriol on calcium and phosphate levels, and what stimulates its release? What is its effect on bone?

A

Increases blood calcium and phosphate levels

Release is stimulated by hypophosphatemia and PTH

Stimulates calcium and phosphate resorption from bone as well due to increased bone turnover

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8
Q

What are the three forms of extracellular calcium and which is freely filtered / biologically active?

A

40% is bound to albumin
10% is complexed to anions like citrate, phosphate, bicarbonate, and lactate
50% is ionized, free calcium

Only the ionized, free calcium is filtered at the glomerulus and is the biologically active amount

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9
Q

How does ionized calcium concentration change with pH?

A

Alkalosis -> albumin is deprotonated, exposing negative charges -> calcium binds albumin more avidly -> hypocalcemia

Acidosis -> opposite -> hypercalcemia

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10
Q

How do you tell if a patient is hypercalcemic or hypocalcemic depending on albumin changes?

A

Use this formula:

“Corrected” Total Calcium = Measured Total Ca + 0.8 (4 - measured albumin)

Calcium in mg/dL
Albumin in g/dL

-> basically it’s giving you the total calcium equivalent @ normal albumin which would generate the free calcium the patient is seeing based on their albumin levels.

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11
Q

What is PTHrP and what cancers secrete it?

A

An unmeasured analog to PTH which was expressed in developing bone, placenta, and fetus

Secreted by: sQuamous cell cancers of lung, head, and neck;
Renal and bladder
Breast and ovarian

Think Q (near P) + urinary + BRCA

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12
Q

What type of receptor is the PTH receptor and why is this clinically relevant?

A

It is a GalphaS receptor

-> increased urinary cAMP can be measured whenever PTH levels are high and the signalling pathway is working properly

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13
Q

What are the symptoms of hypercalcemia to remember?

A
  1. Stones - nephrolithiasis (kidney stones due to hypercalciuria), renal failure (post-renal azotemia)
  2. Thrones - Polyuria (with volume depletion and dehydration)
  3. Groans - abdominal discomfort from kidney stones, acute pancreatitis, nausea/vom
  4. Bones - osteitis fibrosa cystica - see Bosch
  5. Psychiatric overtones: Coma, altered mental status
  6. Metastatic calcification (of normal tissues, i.e. nephocalcinosis)
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14
Q

What are the causes of high serum calcium?

A
  1. Excess PTH
  2. Excess calcium ingestion
  3. Excess vitamin D ingestion
  4. Accelerated bone resorption
  5. Decreased renal excretion and dehydration
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15
Q

What are primary, secondary, and tertiary hyper-PTH usually caused by? (not all of these will be associated with elevated serum calcium levels)

A

Primary - Usually parathyroid adenoma or hyperplasia, less commonly parathyroidism carcinoma.

Secondary - due to hypocalcemia, i.e. renal failure

Tertiary - autonomous hyperparathyroidism from renal disease (nodule becomes autonomous from longstanding secondary)

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16
Q

Give an example of excess calcium causing hypercalcemia?

A

Ingestion of large amount of milk and antacids which contain calcium carbonate can cause hypercalcemia

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17
Q

What are some conditions which can cause excess vitamin D?

A
  1. Vitamin D intoxication

2. Excess endogenous production -> i.e. sarcoidosis, lymphoma (1alpha-hydroxylase activity)

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18
Q

What are some causes of accelerated bone resorption leading to hypercalcemia?

A

Metastatic cancer - invasive lytic bone lesions

Multiple myeloma or Paget’s disease - lytic bone lesions

Immobilization - bone wasting

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19
Q

Why does hypercalcemia tend to make hypercalcemia worse? What medication can make this worse?

A

Polyuria leads to ECF volume depletion -> more Na+ and hence Ca+2 resorption in the proximal tubule

Made even worse by thiazide diuretics -> decrease renal calcium excretion

20
Q

What drug works as a CaSR receptor agonist and what is it used to treat? Side effect?

A

Cinacalcet -> used to treat primary or secondary hyperparathyroidism, makes the body think there is enough calcium (activates CaSR) and it can stop producing PTH.

Side effect is hypocalcemia.

21
Q

What is the initial step in the diagnosis of hypercalcemia? What does each possible outcome mean?

A

Measure PTH.

If PTH high: Primary hyperparathyroidism

If PTH is low: PTH-independent hypercalcemia is the cause

22
Q

What are causes of PTH-independent hypercalcemia? This should be easy

A
  1. Excess calcium intake
  2. Cancer - PTHrP
  3. Increased Vitamin D levels
23
Q

What are the two ways malignancies can cause hypercalcemia?

A
  1. Local osteolytic hypercalcemia - tumor cells invade bone and produce cytokines stimulating osteoclastic bone resorption
  2. Humoral hypercalcemia of malignancy - produce circulating PTHrP, or other cytokines
24
Q

What will happen to urinary calcium levels in primary hyperparathyroidism?

A

They are actually generally increased, because the CaSR is intact and will lead to Ca+2 wasting in the kidney despite high levels of PTH
-> just make more Vitamin D and resorb more bone to keep serum Ca+2 and filtered load of Ca+2 high

25
Q

What are the causes of primary hyperparathyroidism and what will the glands look like in the two most common cases?

A

Parathyroid adenoma - 80% of cases. Single enlarged nodule / one gland enlarged gland, with other three atrophied due to lack of activity

Parathyroid hyperplasia - all four glands are enlarged -> 20% of cases

Parathyroid carcinoma

26
Q

How is an adenoma in PHPT localized?

A

PHPT = primary hyperparathyroidism

Localize via Technetium-99m radionucleotide scan

27
Q

What is the treatment for primary hyperparathyroidism of any cause?

A

Hydration - Ca+2 excretion
Bisphosphonates - suppression of osteoclasts
Cinacalcet

Surgical removal if adenoma

28
Q

What condition is characterized by renal cysts, tumors, and fibro-osseous jaw tumors with PHPT?

A

Hyperparathyroidism-jaw tumor syndrome

29
Q

What are the usual symptoms of hypocalcemia when it’s not severe?

A

Paresthesias around mouth “circumoral” and in fingers and toes -> excitation of the nervous system

30
Q

What are the “signs” associated with hypocalcemia?

A

Trousseau’s sign - PAINFUL (avoid test) carpal SPASM when BP cuff is inflated above systolic pressure for three minutes

Chvostek’s sign - twitching of facial muscles when nerve is tapped at parotid gland (tapping Cheek) -> positive in 10% of normal

31
Q

What are causes of vitamin D deficiency and hence hypocalcemia?

A
  1. Decreased ingestion (malnutrition) or of sunlight
  2. Deficiency of 25-D3 production due to severe liver disease
  3. Anticonvulsant use (CYP inducers) -> breakdown vitamin D
  4. Deficiency of 1alpha hydroxylase activity - advanced renal failure, hypoparathyroidism
32
Q

What is vitamin D dependent vs resistant rickets?

A

Vitamin D dependent - 1alpha hydroxylase deficiency

Vitamin D resistant - vitamin D receptor abnormality

33
Q

What are causes of hypoparathyroidism?

A
  1. Surgical - most common, after total thyroidectomy
  2. Autoimmune
  3. Idiopathic / genetic -> activating mutation of CaSR, or DiGeorge (lack of pouch 3/4)
  4. Infiltration of gland -> iron overload, malignancy
  5. Hypomagnesemia - known cause of low PTH
  6. Pseudohypoparathyroidism
34
Q

What is the cause of pseudohypoparathyroidism type 1A and what is the name of the phenotype?

A

Autosomal dominant defect in Gs protein alpha-subunit -> end-organ resistance to PTH.

Defect must be inherited by MOTHER due to imprinting

Phenotype: Albright hereditary osteodystrophy

35
Q

What is the phenotype of Albright hereditary osteodystrophy (AHO) and what clinical sign is described?

A

Short stature, and short 4th / 5th metacarpals leading to absence of prominent MCP joint
-> knuckle-knuckle-dimple-dimple

36
Q

What is pseudopseudohypoparathyroidism and will they have AHO?

A

Autosomal dominant defect in Gs protein alpha-subunit -> no observed end-organ resistance to PTH, only minor resistance in bone.

They will have the features of AHO

Occurs when the defective Gs subunit is inherited from the father

37
Q

What accounts for the difference between pseudohypoparathyroidism and pseudopseudohypoparathyroidism? How will PTH levels be affected?

A

Kidney - expresses only maternal PTH receptor complex

Bones - express both maternal and paternal PTH receptor complex

Paternal inheritance of mutation -> AHO phenotype, but no kidney issues

PTH levels will be elevated in pseudohypoPT, normal in pseudopseudohypoPT -> kidneys working okay in parental inheritance

38
Q

What lab values characterize secondary hyperparathyroidism and what are some causes?

A

Low serum calcium with high PTH

  1. Chronic Kidney Disease - most common
  2. Vitamin D deficiency
  3. Malabsorption of calcium
  4. PTH resistance - pseudohypoparathyroidism
39
Q

Why does chronic renal disease cause secondary hyperparathyroidism?

A
  1. Low renal perfusion -> hyperphosphatemia
  2. Hyperphosphatemia -> activation of FGF23 -> hypovitaminosis D
  3. Hypovitaminosis D and low Ca+2 -> hyperparathyroidism
40
Q

How do you differentiate between pseudohypoparathyroidism and other conditions with increased PTH but low calcium?

A
  1. Plasma phosphate levels will be elevated (vs vitamin D deficiency and malabsorption)
  2. Urine cAMP will be low (vs kidney failure)
41
Q

What produces FGF23 and what are its actions?

A

FGF23 - produced by osteocytes

Actions:
1. Increased phosphate excretion (inhibited proximal reabsorption)
2. Inhibition of 1-alpha-hydroxyalse
(Basically anti-vitamin D -> can cause rickets and osteomalacia)

42
Q

How is FGF23 degraded and why is this clinically relevant? What is the inheritance pattern?

A

PHEX protein, inherited via X-chromosome.

Dominant mutation that causes resistance of FGF23 to degration -> increased phosphate wasting -> X-linked hypophosphatemic rickets

pg. 55 of first aid

43
Q

What are the symptoms of hyperphosphatemia?

A
  1. Metastatic calcifications -> common in renal failure

2. Suppression of 1-alpha hydroxylase -> hypocalcemia

44
Q

What are the symptoms of hypophosphatemia?

A

Severe muscle weakness due to decreased ATP synthesis -> may cause paralysis and rhabdomyolysis

Hemolysis -> RBCs require ATP to maintain membrane integrity

Bone pain and osteomalacia (hypophosphatemic rickets)

45
Q

What are the causes of hypophosphatemia?

A
  1. Vitamin D deficiency or resistance
  2. Primary hyperparathyroidism or hypercalcemia of malignancy -> increased phosphate wasting
  3. Alkalosis
  4. Excess FGF23
  5. Insulin therapy of DKA
  6. Refeeding syndrome
46
Q

What is the mechanism of hypophosphatemia in refeeding syndrome and insulin therapy in DKA?

A

Both lead to increased glucose uptake and initial phosphoylation of sugars -> phosphate depletion

47
Q

How can alkalosis cause hypophosphatemia?

A

Alkalosis activates PFK-1, causing increased phosphorylation of glucose

  • > most common cause of hypophosphatemia in the hospital
  • > think of it as the body trying to produce lactate in order to restore acid-base status

Pathophysiology - Endocrine and Reproductive (27 decks)

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