Calcium Homeostasis and Disorders of Calcium Metabolism Flashcards
What pharyngeal pouch is the thymus derived from? What else is derived from the same pouch?
3rd pharyngeal pouch
Vental: Thymus
Dorsal: Lower parathyroids
What are three inhibitors of PTH?
- Calcitriol (think of this as negative feedback)
- Hypomagnesia - important because hypomagnesia is a cause of hypocalcemia, and can be treated with Mg+2 supplements
- Hypercalcemia - via calcium sensing receptor
What causes familial hypocalciuric hypercalcemia? What is it characterized by clinically?
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.
What does an activating mutation of the CaSR cause?
Familial hypercalciuric hypocalcemia (opposite of other)
- > PTH is suppressed at lower calcium levels
- > also called hypoparathyroidism with hypercalciuria
How much sun exposure is required to make adequate amounts of vitamin D3?
10-15 minutes of sun exposure at least 2x per weeks on a major body area
-> very little is needed
What happens to 25-hydroxy-D3 in the absence of PTH? What is the test of choice for testing for vitamin D deficiency?
It is converted to inactive 24,25-hydroxy-D3
Testing for 25-OH-D3 (calcidiol) is the test of choice
What is the net effect of calcitriol on calcium and phosphate levels, and what stimulates its release? What is its effect on bone?
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
What are the three forms of extracellular calcium and which is freely filtered / biologically active?
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
How does ionized calcium concentration change with pH?
Alkalosis -> albumin is deprotonated, exposing negative charges -> calcium binds albumin more avidly -> hypocalcemia
Acidosis -> opposite -> hypercalcemia
How do you tell if a patient is hypercalcemic or hypocalcemic depending on albumin changes?
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.
What is PTHrP and what cancers secrete it?
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
What type of receptor is the PTH receptor and why is this clinically relevant?
It is a GalphaS receptor
-> increased urinary cAMP can be measured whenever PTH levels are high and the signalling pathway is working properly
What are the symptoms of hypercalcemia to remember?
- Stones - nephrolithiasis (kidney stones due to hypercalciuria), renal failure (post-renal azotemia)
- Thrones - Polyuria (with volume depletion and dehydration)
- Groans - abdominal discomfort from kidney stones, acute pancreatitis, nausea/vom
- Bones - osteitis fibrosa cystica - see Bosch
- Psychiatric overtones: Coma, altered mental status
- Metastatic calcification (of normal tissues, i.e. nephocalcinosis)
What are the causes of high serum calcium?
- Excess PTH
- Excess calcium ingestion
- Excess vitamin D ingestion
- Accelerated bone resorption
- Decreased renal excretion and dehydration
What are primary, secondary, and tertiary hyper-PTH usually caused by? (not all of these will be associated with elevated serum calcium levels)
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)
Give an example of excess calcium causing hypercalcemia?
Ingestion of large amount of milk and antacids which contain calcium carbonate can cause hypercalcemia
What are some conditions which can cause excess vitamin D?
- Vitamin D intoxication
2. Excess endogenous production -> i.e. sarcoidosis, lymphoma (1alpha-hydroxylase activity)
What are some causes of accelerated bone resorption leading to hypercalcemia?
Metastatic cancer - invasive lytic bone lesions
Multiple myeloma or Paget’s disease - lytic bone lesions
Immobilization - bone wasting
Why does hypercalcemia tend to make hypercalcemia worse? What medication can make this worse?
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
What drug works as a CaSR receptor agonist and what is it used to treat? Side effect?
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.
What is the initial step in the diagnosis of hypercalcemia? What does each possible outcome mean?
Measure PTH.
If PTH high: Primary hyperparathyroidism
If PTH is low: PTH-independent hypercalcemia is the cause
What are causes of PTH-independent hypercalcemia? This should be easy
- Excess calcium intake
- Cancer - PTHrP
- Increased Vitamin D levels
What are the two ways malignancies can cause hypercalcemia?
- Local osteolytic hypercalcemia - tumor cells invade bone and produce cytokines stimulating osteoclastic bone resorption
- Humoral hypercalcemia of malignancy - produce circulating PTHrP, or other cytokines
What will happen to urinary calcium levels in primary hyperparathyroidism?
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
What are the causes of primary hyperparathyroidism and what will the glands look like in the two most common cases?
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
How is an adenoma in PHPT localized?
PHPT = primary hyperparathyroidism
Localize via Technetium-99m radionucleotide scan
What is the treatment for primary hyperparathyroidism of any cause?
Hydration - Ca+2 excretion
Bisphosphonates - suppression of osteoclasts
Cinacalcet
Surgical removal if adenoma
What condition is characterized by renal cysts, tumors, and fibro-osseous jaw tumors with PHPT?
Hyperparathyroidism-jaw tumor syndrome
What are the usual symptoms of hypocalcemia when it’s not severe?
Paresthesias around mouth “circumoral” and in fingers and toes -> excitation of the nervous system
What are the “signs” associated with hypocalcemia?
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
What are causes of vitamin D deficiency and hence hypocalcemia?
- Decreased ingestion (malnutrition) or of sunlight
- Deficiency of 25-D3 production due to severe liver disease
- Anticonvulsant use (CYP inducers) -> breakdown vitamin D
- Deficiency of 1alpha hydroxylase activity - advanced renal failure, hypoparathyroidism
What is vitamin D dependent vs resistant rickets?
Vitamin D dependent - 1alpha hydroxylase deficiency
Vitamin D resistant - vitamin D receptor abnormality
What are causes of hypoparathyroidism?
- Surgical - most common, after total thyroidectomy
- Autoimmune
- Idiopathic / genetic -> activating mutation of CaSR, or DiGeorge (lack of pouch 3/4)
- Infiltration of gland -> iron overload, malignancy
- Hypomagnesemia - known cause of low PTH
- Pseudohypoparathyroidism
What is the cause of pseudohypoparathyroidism type 1A and what is the name of the phenotype?
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
What is the phenotype of Albright hereditary osteodystrophy (AHO) and what clinical sign is described?
Short stature, and short 4th / 5th metacarpals leading to absence of prominent MCP joint
-> knuckle-knuckle-dimple-dimple
What is pseudopseudohypoparathyroidism and will they have AHO?
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
What accounts for the difference between pseudohypoparathyroidism and pseudopseudohypoparathyroidism? How will PTH levels be affected?
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
What lab values characterize secondary hyperparathyroidism and what are some causes?
Low serum calcium with high PTH
- Chronic Kidney Disease - most common
- Vitamin D deficiency
- Malabsorption of calcium
- PTH resistance - pseudohypoparathyroidism
Why does chronic renal disease cause secondary hyperparathyroidism?
- Low renal perfusion -> hyperphosphatemia
- Hyperphosphatemia -> activation of FGF23 -> hypovitaminosis D
- Hypovitaminosis D and low Ca+2 -> hyperparathyroidism
How do you differentiate between pseudohypoparathyroidism and other conditions with increased PTH but low calcium?
- Plasma phosphate levels will be elevated (vs vitamin D deficiency and malabsorption)
- Urine cAMP will be low (vs kidney failure)
What produces FGF23 and what are its actions?
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)
How is FGF23 degraded and why is this clinically relevant? What is the inheritance pattern?
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
What are the symptoms of hyperphosphatemia?
- Metastatic calcifications -> common in renal failure
2. Suppression of 1-alpha hydroxylase -> hypocalcemia
What are the symptoms of hypophosphatemia?
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)
What are the causes of hypophosphatemia?
- Vitamin D deficiency or resistance
- Primary hyperparathyroidism or hypercalcemia of malignancy -> increased phosphate wasting
- Alkalosis
- Excess FGF23
- Insulin therapy of DKA
- Refeeding syndrome
What is the mechanism of hypophosphatemia in refeeding syndrome and insulin therapy in DKA?
Both lead to increased glucose uptake and initial phosphoylation of sugars -> phosphate depletion
How can alkalosis cause hypophosphatemia?
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
