Parathyroid and Mineral Metabolism Disorders Flashcards
function of parathyroid gland?
synthesis and release of parathyroid hormone (PTH) to maintain extracellular fluid calcium concentration
describe the negative feedback loop of the parathyroid gland
- Stimulation of the receptor by high calcium levels reduces PTH secretion
- lack of receptor stimulation by low calcium levels lead to increased PTH
the negative feedback loop of the parathyroid gland is controlled by what?
serum ionized calcium, which interacts with calcium sensing receptor (CaSR) in the parathyroid and kidney.
Parathyroid hormone secretion in response to ?
What are the responses?
hypocalcemia
1. Immediate (minutes) release of preformed PTH
2. Delayed (hours) PTH mRNA expression increases synthesis of PTH
3. Extended (days) parathyroid cell replication increasing parathyroid gland mass
function of calcium
- maintain bone and teeth strength
- promotes contraction and relaxation of muscle and blood vessels
- hormone and enzyme secretion
- neurocellular signaling
Calcium (Ca²⁺) is stored in 3 major areas:
-
bone
- majority (99%) is stored in the mineral phase of the bone -
intracellular
- assists with intracellular signaling, enzyme activation and muscle contractions -
blood/extracellular fluid
- 50% of Ca²⁺ is bound to proteins
- serum levels fluctuate easily - balance is maintained by release from cellular storage or influx from extracellular fluid
what are the 3 organs work together to maintain a very narrow range of extracellular Ca²⁺
- intestines - absorbs dietary Ca²⁺
- kidneys - reabsorbs Ca²⁺ in the tubular system, preventing excretion
- bone - reservoir for Ca²⁺, releasing and reserving as needed
where does Phosphate absorption/excretion
happen?
- absorbed in small intestines from food
- excreted by kidneys
absorption of phosphate requires what
vitamin D
where is phosphate stored?
- 85% - mineral phase of bone
- 15% - intra- and extracellular compartments
Phosphate function
- bone and teeth formation
- building block for cell for energy, cell membranes, and DNA
what are the 3 hormones that maintain the balance of calcium and phosphate
- Parathyroid Hormone (PTH)
- Vitamin D -1,25
- Calcitonin
what is PTH effect on the kidney?
- promotes reabsorption of calcium (Ca²⁺) in the kidney
- promotes excretion of phosphate (PO₄₃₋) in the kidney
- stimulates production of Vitamin D-1,25
what is PTH effect on the bone?
stimulates the movement of Ca²⁺ and PO₄₃₋ from the bone to extracellular circulation
Vitamin D 1,25 comes from where
Converted from inactive Vitamin D-25 by PTH and released from the kidneys
function of Vitamin D 1,25
- Increases intestinal absorption of dietary calcium and phosphorus
- Enhances effect of PTH on movement of Ca²⁺ out of bone
calcitonin-secreting cells (C cells) comes from where?
thyroid
When C-cells are overstimulated what happens?
elevated calcium levels stimulate C-cells = Calcitonin released by the thyroid
Calcitonin function
- works in opposition to PTH
- suppresses renal reabsorption of Ca²⁺, increasing Ca²⁺ excretion
- inhibits osteoclastic activity = decrease release of Ca²⁺ from bone, increases bone calcium storage
serum calcium includes ?
- Total serum calcium = protein bound Ca²⁺ + free Ca²⁺
- 40 - 50% are protein bound (albumin and globulin)
- Ionized or “free” (active) calcium
what can cause Falsely abnormal results of serum calcium?
- elevation
- hemoconcentration and elevated serum proteins (albumin) - depression
- low serum proteins
abnormal albumin requires a “calculated” calcium level
Current standard for diagnosis of hyperparathyroidism
Serum PTH
Sensitivity and specificity are very high
increased serum PTH is indicative of?
Primary and secondary hyperparathyroidism
decreased serum PTH is indicative of?
Hypoparathyroidism, hypercalcemia not due to hyperparathyroidism
what are the 2 forms of Vitamin D included in serum 25-hydroxy vitamin D?
- D3 (cholecalciferol), synthesized in the epidermis
- can vary based upon amount of sun exposure - D2 (ergocalciferol), derived from plant sources
Increased Calcitriol (1,25-dihydroxy-vitamin D) can be from what?
- direct intake of this metabolite
- extrarenal production in granulomatous diseases or lymphoma
- increased renal production induced by hyperparathyroidism
decreased Calcitriol (1,25-dihydroxy-vitamin D)
can be from what?
- CKD, severe vitamin D deficiency
- various heritable disorders, tumor-induced osteomalacia
- the use of HIV protease inhibitors
how would you interpret abnormal (increased/decreased) serum phosphate levels?
- increased: hypoparathyroidism
- decreased: hyperparathyroidism
Interpretation: multiple causes for elevated or depressed levels
what hormone is pathologically secreted by cancer cells and attaches to the PTH receptors resulting in a PTH effect on the bone and kidney
Parathyroid Hormone Related Protein (PTHrP)
what condition would you see an increased PTHrP
Humoral Hypercalcemia of Malignancy
how does parathyroid related conditions (adenomas, lithium) cause hypercalcemia?
secretion of PTH
1. over secretion of PTH due to increased parathyroid mass
2. decreases parathyroid gland sensitivity to calcium
how do malignancy related conditions cause hypercalcemia
osteolysis, release of PTH related protein
how do Vitamin D related conditions cause hypercalcemia?
Vitamin D increases dietary calcium absorption and bone resorption
how do high bone turnover conditions (hyperthyroidism, immobilization, thiazides) cause hypercalcemia?
bone resorption - osteoclastic break down of the bone
1. thyroid hormone stimulated bone resorption
2. bone resorption due to lack of use
3. decreases urinary calcium excretion in addition to bone resorption
how do renal failure conditions (tertiary hyperparathyroidism, milk-alkali syndrome) cause hypercalcemia?
- hyperplasia of the parathyroid glands from prolonged CKD persisting in elevated PTH despite normalization of calcium with CKD treatment
- calcium carbonate supplementation to treat osteoporosis or dyspepsia
presentation of hypercalcemia
“Bones, Stones, Groans and Psychiatric overtones”
tx of hypercalcemia
- Look for and treat underlying condition
- Severe hypercalcemia (symptomatic or Ca²⁺ > 14 mg/dL)
- IV NS 500-1000 ml/h x 2-4 hours as tolerated
- +/- Furosemide
— risk of paradoxical increase in Ca²⁺ due to bone resorption
— monitor for hypokalemia and hypomagnesemia
- +/- Corticosteroids - tx of choice for cases of calcitriol-mediated hypercalcemia
— decreases conversion of inactive to active vitamin D - Very severe cases may require hemodialysis - consult nephrology
hypercalcemia is MC caused by ?
hyperparathyroidism and malignancy
90% of cases
hypocalcemia is MC caused by ?
impaired PTH and Vitamin D production
Hypocalcemia caused by low PTH (hypoparathyroidism) is a result from what?
- parathyroid agenesis
- parathyroid destruction
- surgical, radiation, cancer, autoimmune - Reduced parathyroid function
- hypomagnesemia
hypocalcemia caused by high PTH (econdary hyperparathyroidism) is a result from what?
- Vit D deficiency: nutritional, renal insufficiency
- Tissue injury: burns, tumor lysis, pancreatitis, rhabdomyolysis
- parathyroid hormone resistance
- PTH receptor mutations -
Drugs
- calcium chelators
- inhibitors of bone resorption
— bisphosphonates - used to treat osteoporosis
clinical findings of hypocalcemia
neuromuscular irritability
1. paresthesias: fingers, toes, circumoral region
2. Chvostek’s sign - Facial twitching, especially around the mouth
3. Trousseau’s phenomenon - Carpal spasm induced by inflating BP cuff
labs to get for Hypocalcemia
- PTH level
- Albumin, creatinine
- Phosphorus, Magnesium
- Vitamin D: both serum 25-hydroxyvitamin D and serum 1,25(OH)2D levels
condition that shows excessive PTH secretion leads to hypercalcemia and hypophosphatemia
Primary Hyperparathyroidism
MC cause of hypercalcemia
Primary Hyperparathyroidism
MC in females between 60-70 years of age (74%)
MC etiology of Primary Hyperparathyroidism
single parathyroid adenoma
presentation of Primary Hyperparathyroidism? palpable/nonpalpable neck mass means what?
- asx - MC
- symptoms related to hypercalcemia
- parathyroid adenoma - no palpable mass
- parathyroid carcinoma - palpable neck mass
labs with Primary Hyperparathyroidism
- corrected serum calcium or ionized calcium
- elevation correlates with size of adenoma
- carcinoma = ≥14.0 mg/dL - PTH
- elevation confirms diagnosis
- correlates with size of adenoma
- carcinoma - 5x ULN - 24 hour urine calcium
- >200-300 - likely PHPT - excludes FHH
- <200 - FHH or PHPT with vit D deficiency
- stop loop/thiazide diuretics prior to testing - serum phosphate
- helps differentiate primary from secondary
- low (< 2.5 mg/dL) - primary hyperparathyroidism
- high (>4.5 mg/dL) - secondary hyperparathyroidism due to CKD - Serum 25-OH vitamin D
- often decreased due to excessive conversion of Vit D 25 to vit D 1-25 - Serum creatinine and estimated glomerular filtration rate (eGFR)
- assess renal function - imaging (not necessary for diagnosis)
- Used only once surgery is decided as the tx
- Neck ultrasound - more helpful for single adenomas
- Nuclear Medicine Parathyroid Scan
- CT - 4D
what imaging technique uses nuclear tracer Tc99m-sestamibi and SPECT (3-D) imaging
Hyperfunctioning parathyroid glands will light up compared to normal tissue
Nuclear Medicine Parathyroid Scan
which imaging technique is used only if US and parathyroid scan are negative or if concern for ectopic parathyroid adenomas/carcinomas
CT - 4D
management for asx Primary Hyperparathyroidism
- regular weight bearing exercise, avoid immobilization, and drink adequate fluids
- Avoid
- thiazide diuretics
- large doses of vitamin A
- calcium-containing antacids/supplements - Routine monitoring
- Serum calcium and albumin 2x/yr
— if increasing initiate further workup
- Renal function and urine calcium yearly - surgical intervention is recommended if urine Ca is > 400 mg/d
- Serum Vit D 25 - replace if low (< 20 ng/mL)
- Three site Dual Energy X-ray Absorptiometry (DEXA) scan (distal radius, hip, and spine) every 2 years
— if (+) for osteoporosis/-penia = bisphosphonates
— if (-) = assess spine for pathologic vertebral fractures
tx for symptomatic Primary Hyperparathyroidism
- Parathyroidectomy
- symptomatic hyperparathyroidism
- kidney stones
- bone disease
- persistent urinary calcium > 400 mg/dL
- pregnancy - Nonsurgical measures
- cinacalcet (Sensipar)
- Oral Bisphosphonates
- IV Bisphosphonates
- For postmenopausal women
— Estrogen replacement
— Raloxifene (Evista)
what med binds to CaSRs in the parathyroid gland, increasing the glands’ affinity for extracellular calcium, thereby decreasing PTH secretion
cinacalcet (Sensipar)
alendronate (Fosamax)
oral bisphosphonates
ibandronate (Boniva)
oral Bisphosphonates
what med can be used to improve bone mineral density (BMD)
indicated only if low BMD and pt is unable to undergo surgery
must be able to remain upright for 30 min after ingestion
Oral Bisphosphonates
which med is ineffective for hypercalcemia or hypercalciuria
oral Bisphosphonates
pamidronate (Aredia)
IV Bisphosphonates
zoledronic acid (Reclast)
IV Bisphosphonates
what med
is a potent inhibitor of bone resorption and can temporarily treat hypercalcemia
Often used for severe hyperparathyroidism in preparation for surgery
IV Bisphosphonates
- Induce a gradual decline in serum calcium over several days that may last for weeks to months
which primary hyperparathyroidism tx shows an increased risk of breast and uterine cancer
estrogen replacement
what med
acts as an estrogen agonist in the bone to decreases bone resorption reducing serum Ca+
acts as an estrogen antagonist in the breast and uterine tissue
Raloxifene (Evista) - estrogen agonist/antagonist
complications with Primary Hyperparathyroidism
-
Osteopenia/osteoporosis/pathological fractures
- evaluate with (DEXA) scan routinely - every 2 years
- vertebra - highest risk for pathologic fracture
— assess with plain film x-ray if suspected fx
- tx = oral bisphosphonates -
Vit D deficiency
- evaluate with serum Vit D-25
- tx = Vit D replacement therapy - Nephrolithiasis
- refer to nephrology if symptomatic
presentation of Secondary Hyperparathyroidism
- often related to underlying condition and less likely to be related to hyperparathyroidism
- symptoms of hypocalcemia if present
MC cause of Secondary Hyperparathyroidism
CKD
- poor reabsorption of calcium (hypocalcemia)
- inhibited excretion of phosphate (hyperphosphatemia)
- inadequate conversion of Vit D-25 to Vit D-1,25 (inability to absorb dietary calcium)
(less often due to vitamin D deficiency)
labs for secondary hyperparathyroidism
- BUN/Cr - elevated in CKD
- PTH, calcium, phosphorus, Vit D-1,25
- high PTH, low-normal Ca
- phosphorus - high in CKD; low in Vit D def
- Vit D-1,25 - low in CKD
how do you r/o pathologic fractures for secondary hyperparathyroidism
Imaging - radiograph of areas of bone pain
management of Secondary Hyperparathyroidism
- Refer to nephrology for CKD if present
- Medical management is the mainstay of therapy
- Vit D supplement
- Dietary restriction of phosphate (if CKD) - Surgical management
- indicated if symptomatic and a failure of medical therapy and control of underlying condition
causes of Hypoparathyroidism
- Acquired - s/p thyroidectomy, parathyroidectomy
- often transient but can be permanent - Autoimmune hypoparathyroidism
- Parathyroid deficiency
- irradiation, heavy metal exposure (copper, iron), granulomas, Riedel thyroiditis, metastatic cancer or infection - Functional hypoparathyroidism
- severe hypomagnesemia creates a “false”block of CaSR which inhibits PTH release
- hypermagnesemia suppresses PTH release - pathophysiology unknown - Congenital - multiple conditions resulting in agenesis, hypoplasia or genetic mutant dysfunction of CaSR
presentation of Hypoparathyroidism
- Severity of symptoms are directly proportional to the calcium level
- Hallmark of acute hypocalcemia is tetany due to neuromuscular irritability
- Symptoms
- mild - paresthesias
- severe - spasms/seizures - PE
- Troussseau’s
- Chvostek’s
labs for Hypoparathyroidism
-
Serum calcium - low
- Ionized or corrected calcium - Serum phosphorus - high
- Urinary calcium - low
- PTH - low
- Vitamin D 1,25 - normal to low (depending on severity)
- Magnesium, Vitamin D-25, Creatinine - normal
- EKG - prolonged QT and T wave
- depending on severity of hypocalcemia
Acute Management for Hypoparathyroidism
- Maintain airway
-
IV Calcium gluconate 10% sln
- Indications - tetany, seizures, refractory heart failure, prolonged QT interval, laryngospasm, bronchospasm or serum Ca ≤ 7.5 mg/dL
- adjust rate to keep serum Ca between 8–9 mg/dL -
Oral Calcium
- given ASAP to supply 1–2 g of calcium daily
— calcium carbonate or calcium citrate - Magnesium (if hypomagnesemic)
- Hypomagnesemia must be treated if present
— severely low levels = prevents PTH release
— worsens hypocalcemia and hypoparathyroidism
- Initial mod-severe: magnesium sulfate IV
- Followed by: magnesium oxide -
Vitamin D Therapy
- start as soon as oral calcium is begun
— Calcitriol (vit d-1,25) - quick onset and shorter duration of action
—— doesn’t require renal activation
Maintenance Therapy for Hypoparathyroidism
- Calcium therapy 1-2 grams daily
- for symptomatic patients or Ca < 8.0 mg/dL
- monitor serum calcium every 3-6 months
— goal = keep Ca lvl slightly low/asymptomatic level 8-8.6 mg/dL
— restoration of “normal” calcium levels will result in hypercalciuria and renal stones - Continue vitamin D supplements
- Monitor serum Mg - replace as needed
- rhPTH - Teriparatide (Forteo) SQ
- indicated for pt refractory to Ca/Vit D
while on calcium therapy, how can you check for calcium toxicity?
monitor with “spot” urinary calcium level
Prevention for hypoparathyroidism
Transplant of cryopreserved parathyroid tissue
1. for pt undergoing a parathyroidectomy due to hyperplasia resulting in permanent hypoparathyroidism
2. often transplanted in the forearm (brachioradialis)
- alternative locations: pectoralis , SCM
Drisdol
Vitamin D 2
Calciferol
Vitamin D 2
ergocalciferol
Vitamin D 2
dosing for Vitamin D 2
- Vitamin D Deficiency - 1,500 - 2,000 IU PO once daily; start 50,000 IU weekly until normal levels are obtained
- Hypoparathyroidism - 50,000-200,000 IU PO once daily with calcium supplements
MOA of vitamin D 2
Stimulates calcium and phosphate absorption from small intestine
stimulates phosphate reabsorption at renal tubule
stimulates secretion of calcium into blood from bone
PK of vitamin D 2
- Absorption - Peak effect: 1 month with daily dosing
- Metabolism - liver
- Elimination - Urine
SE of Vitamin D 2
- usually well tolerated
- arrhythmias, confusion, constipation, dry mouth, headache, hypercalcemia, lethargy, metallic taste, muscle or bone pain, nausea, sluggishness, vomiting
CI of vitamin D 2
Hypercalcemia, Hypervitaminosis D
active form of vitamin D (1,25)
Calcitriol
MOA of Calcitriol
Binds to and activates the vitamin D receptor in the kidney, parathyroid gland, intestine, and bone, stimulating intestinal calcium transport and absorption
SE of calcitriol
hypercalcemia, headache, polydipsia, abdominal pain, nausea
CI of calcitriol
Hypersensitivity to calcitriol, Hypercalcemia, Hypervitaminosis D
dosing for Calcium Carbonate
Hypocalcemia Prevention/Treatment - 1-2 g/day in divided doses
what is a dietary supplement: prevents or treats negative Ca balance
Calcium Carbonate
SE of Calcium Carbonate
hypotension, HA, constipation, N/V/D, flatulence, hypophosphatemia, hypomagnesemia, hypercalcemia
dosing for Calcium Gluconate
- Without seizure or tetany: 0.5 mg/kg/hr IV; may be increased to 2 mg/kg/hr; not to exceed 3-4 g IV over 4 hours
- Hypocalcemic tetany/seizure: 100-300 mg elemental calcium (~3 g calcium gluconate) IV over 5-10 minutes, followed by continuous IV infusion at 0.5 mg/kg/hr (may be increased to 2 mg/kg/hr)
dosing for Magnesium Oxide
Magnesium Supplementation: 400-800 mg PO qd (max 800 mg/d)
Dietary supplement: prevents or treats negative Mg balance
Magnesium Oxide
SE of Magnesium Oxide
Diarrhea with excessive dose, gastrointestinal irritation
