Parathyroid, Calcium, & Vitamin D Disorders

Question 1

Hyperparathyroidism

Answer 1

• Definition: excess PTH that leads to bone resorption → excess serum calcium
• Etiology:
  
  • Primary:
    
    • parathyroid adenoma = most common, parathyroid hyperplasia (rare), Lithium, MEN I (mutation of the transcription factor MENIN, autosomal dominant), MEN-2A (mutation of the RET gene, autosomal dominant), parathyroid carcinoma
  • Secondary:
    
    • parathyroid gland is normal but makes excess parathyroid hormone in response to chronic hypocalcemia (ex. CKD, low vit D)
• S/sxs:
  
  • Mostly asymptomatic
    
    • sxs of hypercalcemia: stones, bones, abdominal groans, and psychiatric overtones
• PE:
  
  • decreased deep tendon reflexes ( neurons less excitable d/t excess Ca2+)
  • dehydration: excess loss of Ca2+
• Dx:
  
  • Triad: hypercalcemia, increased intact PTH, hypophosphatemia
  • Diagnostics:
    
    • Parathyroid scan: technetium-99 sestamibi
      
      • → imaging for parathyroid adenomas
    • neck US: helps find 2+ adenomas & 4 gland sensitivity
• Tx:
  
  • Observation (asymptomatic, low risk): annual serum calcium, DEXA q1-2 years, annual eGFR & creatinine
  • Primary hyperthyroidism: referral to endo
  • Indications for surgery in primary hyperparathyroidism: see other note card

Question 2

Indications for Surgery in Primary Hyperparathyroidism

Answer 2

• Overt clinical manifestations of disease (kidney stone, fractures, neuromuscular disease)
• Serum Calcium > 1.0 mg/dL the UNL
• CrCl < 60 mL/min
• BMD: T-score < -2.5 at spine, hip, or radius
• Age: < 50 years old

Question 3

Hypoparathyroidism

Answer 3

• Definition: deficient parathyroid hormone
• Etiology:
  
  • post-surgical (thyroidectomy, parathyroidectomy), autoimmune destruction of parathyroid gland, radiation therapy, hypomagnesemia
• S/sxs:
  
  • sxs of hypocalcemia:
    
    • paresthesias, carpopedal spasm, tetany, irritability
• PE:
  
  • Trousseau sign: carpopedal spasm caused by an inflated BP cuff above systolic pressure for 3 minutes
  • Chvostek sign: twitching of facial muscles when someone taps on the facial nerve
  • Increased deep tendon reflexes
• Dx:
  
  • Triad:
    
    • hypocalcemia, decreased intact PTH, hyperphosphatemia
  • ECG: prolonged QT interval
• Tx:
  
  • Mild: oral calcium 4g/day (divided doses to take with meals) best taken with food & activated vitamin D supplementation
  • Severe or Symptomatic: IV calcium gluconate or IV calcium carbonate

Question 4

PTH mediated hypercalcemia: Etiology, s/sxs, PE

Answer 4

• Etiology:
  
  • Primary hyperparathyroidism (most common in outpatient): adenoma, hyperplasia, carcinoma
  • Familial hypocalciuric hypercalcemia (FHH):
    
    • `autosomal dominant inactivating mutation in Ca-sensing receptor gene expressed in parathyroid, renal, & bone → higher threshold for rising Ca to stop PTH production; will have high serum Ca & low urine calcium
  • Medications:
    
    • lithium (stimulates PTH secretion, occurs years after tx), theophylline, bisphosphonates, calcitriol, dietary Ca + vit D
• S/sxs:
  
  • mostly asymptomatic
  • Stones:
    
    • renal stones, nephrocalcinosis, polyuria, polydipsia, uremia
  • Bones:
    
    • bone pain & fractures (osteoporosis, osteomalacia, arthritis)
  • Abdominal groans:
    
    • peptic ulcer, constipation, indigestion, N/V
  • Psychiatric Overtones:
    
    • lethargy, fatigue, depression, psychoses, confusion, stupor, coma
  • Decreased DTR
  • proximal muscle weakness
  • HTN
• PE:
  
  • pt with mild calcium elevation (10.5-11) have few to no sxs
  • calcium > 11 may have symptoms

Question 5

PTH mediated hypercalcemia: Dx & Tx

Answer 5

• Dx:
  
  • Diagnostics:
    
    • 24 hour urine calcium: to detect renal stones
    • Consider 1,25-OH vitamin D, PO4, alkaline phosphatase,, MM
    • consider DEXA scan if > 50 yo (wrist-high cortical bone)
  • if hypercalcemia is found → recheck serum calcium with correction for albumin or ionized calcium or ionized calcium → check PTH, CMP, phosphorous, & 25-OH vitamin D levels
  • PTH low (<25): PTH independent
  • PTH normal/high: PTH dependent
    
    • adenoma = higher ca2+ level needed to trigger a decrease in PTH production
  • *20% of patients will have a PTH in the reference range but at the higher end (but it is inappropriately high given serum calcium levels)
• Tx:
  
  • d/c offending meds/supplements if possible, repeat calcium level 2-3 weeks later
  • moderate/severe:
    
    • IV fluids, IV loop diuretics
  • Lithium-associated hypercalcemia:
    
    • if mild then can observe calcium levels, if overt then stop the lithium b/c patient is at risk nephrogenic diabetes insipidus (only reversible if caught early)
  • Familial Hyperparathyroidism:referralto endocrinologist for genetic testing if it runs in the family

Question 6

PTH Independent Hypercalcemia

Answer 6

• Etiology:
  
  • Malignancy (most common → inpatient) , local osteolytic disease
  • -Vitamin D intoxication (~100,000 IU daily)
  • Hyperthyroidism (thyrotoxicosis): thyroid hormone elevation leads to increased bone resorption
  • immobility
  • chronic renal failure, mediations (Thiazides )
• S/sxs:
  
  • mostly asymptomatic
  • Stones: renal stones, polyuria, polydipsia, uremia
  • Bones: bone pain & fractures (osteoporosis, osteomalacia, arthritis)
  • Abd groans: peptic ulcer, constipation, indigestion, N/V
  • Psychiatric overtones: lethargy, fatigue, depression ,psychoses confusion
  • Decreased DTR, proximal muscle weakness, HTN
• Dx:
  
  • if Hypercalcemia found → recheck serum calcium with correction for albumin or ionized calcium → check PTH, CMP, phosphorous & 25-OH Vitamin D Levels
  • PTH low (<25): PTH independent
  • Malignancy Dx:
    
    • CXR (squamous cell lung cancer)
    • PTH-related protein (PTH-rp); made by some tumor types, mimics PTH to increase osteoclast activity
    • SPEP/UPEP (EP = electrophoresis) → to assess for MM
    • Mammogram
    • abd/chest CT
• Tx:
  
  • hypercalcemia of malignancy
    
    • endocrine & oncology consult
  • hyperthyroidism:
    
    • beta-blockers
  • Vitamin D intox:
    
    • can take weeks to resolve since it is stored in fat & released slowly
  • Thiazide-Induced: stop thiazide & recheck calcium level in a few weeks

Question 7

Paget’s Disease

Answer 7

• aka osteitis deformans
• Definition: increased osteoclastic bone resorption & increased osteoblastic bone reformation → larger but weaker bones
  
  • usually presents after long periods of bed rest or fracture
• S/sxs:
  
  • usually asymptomatic
  • bone pain, skull enlargement
• Dx:
  
  • Normal Baseline Calcium & Phosphorus
  • usually found incidentally in older adults (>55yo)
  • Alk phos: elevated
  • Xray: cotton wool appearance d/t mixed lytic & sclerotic lesions
  • mosaic lamellar bone pattern
• Tx:
  
  • Asymptomatic: no tx
  • symptomatic: bisphosphonates
• 15-20% of Paget’s patients have primary hyperparathyroidism causing hypercalcemia

Question 8

Hypocalcemia

Answer 8

• Etiology:
  
  • Hypoparathyroidism: post-surgical (most common)
  • Renal Insufficiency that leads to resistance to PTH action
  • Vitamin D Deficiency (most common)
• S/sxs:
  
  • Paresthesias (face, hands, feet)
  • tetany: carpopedal spasm, laryngospasm
  • seizures, muscle cramps, GI: abd pain, diarrhea, cramps
  • Skeletal: abnormal dentition, osteomalacia, osteodystrophy
• PE:
  
  • Trousseau’s Sign: carpopedal spasm caused by inflating BP cuff for 3 minutes
  • Chvostek’s Sign: twitching over facial muscles in response to tapping on the facial nerve
• Dx:
  
  • Labs to order: Serum calcium (corrected for albumin), phosphate, magnesium (needed for PTH production), electrolytes, SCr, alk phos, PTH, 25-hydroxyvitamin D, serum pH, CBC
  • EKG = prolonged QT
• Tx:
  
  • Mild: oral calcium carbonate (for most) 4g/day (divided doses to take with meals
    
    • supplementation of 25-OH Vitamin D once stable
  • Severe or symptomatic: IV calcium gluconate or IV calcium carbonate
  • may need Mg replacement
  • may need calcitriol 0.25mcg PO BID (to replace 1,25-OH Vitamin D) if serum calcium still low after tx

Question 9

Physio note: how does Ca2+ affect cell membrane excitability

Answer 9

calcium stabilizes the membrane; high calcium = less excitable, low calcium = more excitable.

Question 10

Vitamin D Deficiency

Answer 10

• Etiology:
  
  • Reduced skin synthesis: sunscreen, skin pigment, aging, seasons, burns, inadequate exposure to sunlight (Major drugs)
• S/sxs:
  
  • mostly asymptomatic
    
    • bone pain & tenderness
    • muscular weakness
    • bowing of long bones
• Dx:
  
  • 25-OH Vitamin D: low
  • calcium: low
  • phosphate: low
• Tx:
  
  • Prevention:
    
    • Vitamin D supplementation in older adults for fall prevention
    • no dose-response relationship b/w vit D & bone health for 19-50yo
  • Vitamin D repletion:
    
    • insufficiency: 600-1000 IU PO daily
    • deficiency: 50,000 IU PO weekly x 8 weeks
    • Recheck 25-OH vitamin D levels 3-4 months after starting treatment

Question 11

When to Screen for Vitamin D deficiency

Answer 11

screening not recommended for individuals who are not at risk for 25-OH vitamin D deficiency → target testing of a serum 25-OH vitamin D level is appropriate for at-risk patient populations & if clinically indicated

• indications:
  
  • rickets, osteomalacia, osteoporosis, chronic kidney stones, hepatic failure, hyperthyroidism, Pregnancy, obese, older adults with hx of falls or non-traumatic fractures

Question 12

Vitamin D levels (25-OH) that indicate sufficient levels, insufficient and deficient

Answer 12

• sufficient: 30-50 ng/mL (>50 ng/mL = not beneficial)
• insufficient: 21-29 ng/mL
• deficient: <20 ng/mL

Question 13

Is 1,25-OH Vitamin D indicated for routine eval of vitamin D deficiency

Answer 13

no, b/c it is a poor indicator of sufficiency

Question 14

Vitamin D supplement sources

Answer 14

• Exposure to sunlight: 3000 IU vitamin D3
• Multivitamin: 400-1000 IU D, D2 or D3
• OTC supplement: 400-2000 IU
• Ergocalciferol rx: 50K IU D2
• Cholecalciferol rx: 40-10,000 IU D3
• **SE: upset GI → take with juice

Question 15

Vitamin D Excess

Answer 15

• Definition: serum 25-OH vitamin D levels > 150 ng/mL concerning for toxicity
• Etiology:
  
  • vitamin D doses > 50,000 IU/day → most are iatrogenic
  • Vitamin D increases both Ca2+ & phosphate
• S/sxs:
  
  • hypercalciuria/emia
  • AMS
• PE:
  
  • chronic excess → tissue calcification which leads to CV & renal damage
• Dx:
  
  • 25-OH Vitamin D: high
  • Calcium: high
  • PTH: low
• Tx:
  
  • d/c supplementation

Question 16

Osteoporosis: Def, Pathophys, S/sxs

Answer 16

• Definition:
  
  • a disease characterized by low bone density & deterioration of bone tissue → enhanced bone fragility → increase of risk of fracture
• Pathophys:
  
  • There is an imbalance between the osteoblasts (builders) & osteoclasts (chewers); decreased osteoblast formation & shortened lifespan, increased fat formation, decreased levels/activity of sex-steroid hormones & Vit D
• Fractures:
  
  • vertebra (27%), wrist (19%), hip (14%)
• S/sxs:
  
  • usually asymptomatic
  • bone fractures: pathologic fractures (vertebra, hip, radius)
  • spine compression: loss of vertebral height, kyphosis, back pain

Question 17

FRAX Risk Assessment

Answer 17

used in osteoporosis

helps determine 10-year probability of a hip fracture or major osteoporosis-related factor (does NOT tell you whether to treat)

• factors: age, gender, weight, height, parent who fractured a hip, smoking, glucocorticoid useage, RA, secondary osteoporosis, femoral neck BMD or T-score
• Risks:
  
  • Low risk:
    
    • no prior hip or spine fractures, BMD T-score above -1.0, 10 year hip fracture risk < 3%, 10 year risk of major osteoporotic fractures < 20%
  • Moderate Risk:
    
    • no prior hip or spine fractures, BMD T-score above -2.5, 10 year hip fracture risk < 3%, 10 year risk of major osteoporotic fractures < 20%
  • High Risk:
    
    • a prior hip or spine fractures, BMD T-score below -2.5, 10 year hip fracture risk ≥ 3%, 10 year risk of major osteoporotic fractures ≥ 20%
  • Very High Risk:
    
    • multiple spine fractures & a BMD T-score at the hip or spine of -2.5 or below

Question 18

When to Screen for Osteoporosis:

Answer 18

All women ≥ 65 yo and all men ≥ 70 yo

• All post-menopausal women with: hx of fractures without major trauma, osteopenia identified radiographically, long-term glucocorticoid therapy (>3 mo)
• Secondary osteoporosis (many causes): endocrine, nutrition, drugs, etc.
• Consider in postmenopausal women with:
  
  • low body weight (<127 lbs), family hx of osteoporotic dx, early menopause, smoking, excessive alcohol usage

Question 19

Osteoporosis: Dx & Tx

Answer 19

• Dx:
  
  • in the absence of fracture, osteoporosis is T-score ≤ -2.5 in the AP spine, femoral neck, or total hip
    
    • Normal: T score ≥ -1.0
    • Osteopenia: T score -1.0 to -2.4
  • in the presence of fracture of the hip or spine when there is an absence of other conditions i.e. trauma
• Tx:
  
  • Who to tx:
    
    1. Pt with fragility fracture of hip/spine,
    2. T-score ≤ -2.5 in AP spine/hip
    3. chronic glucocorticoid use of > 5 mg/day for > 3 months
       
       • consider tx if FRAX calculates:
         
         • 10-year probability of osteoporosis-related fracture > 20%
         • 10-year probability of hip fracture ≥ 3%
  • 1200 mg elemental calcium daily (divided into doses with meals)
  • -800-1000 IU vitamin D daily
    
    • (treat to 30-50 ng/mL)
  • Antiresorptive therapies:
    
    • Bisphosphonates (PO or IV, risk of osteonecrosis of jaw & atypical femoral fracture)
    • Denosumab (SQ Q6 months, once started can’t stop b/c it increases risk of fracture
  • Anabolic therapies:
    
    • teriparatide (SQ qday x 2 years ONLY)
    • abaloparatide (SQ qday x 2 years ONLY)
  • Calcitonin:
    
    • spine fracture risk reduction only
      
      • best used in tx acute pain from spinal compression fractures
  • Estrogen
    
    • not recommended
• Monitoring:
  
  • DEXA scan Q1-2 years

Question 20

How does a DEXA scan work and score pts?

Answer 20

• DEXA: dual-energy xray absorptiometry of the hip & spine (central)
• BMD: determines bone strength (along with quality)
• T-score: SD difference between a patient’s BMD & young adult
• Z-score: SD difference between a patient’s BMD & age matched population
• Scoring:
  
  • Normal: T score ≥ -1.0
  • Osteopenia: -1.0 to -2.4
  • Osteoporosis: T-score ≤ -2.5

Question 21

Treatment of Secondary HyperPTH and bone disorders

Answer 21

• Goals
  
  • Maintain corrected Ca, Phos, and PTH levels as close to normal as possible
    
    • Ca2+ corrected = Ca2 obs + 0.8 (4-obs albumin)
      
      • normal range: 8.5-10.3mg/dL
      • phos normal range: 2.5-4.5mg/dL
      • PTH normal range: 11-54 pg/mL
• Dietary Phosphorus restriction: 800-1000mg/d
• avoid aluminum exposure: i.e. antacids
• Last resort = parathyroidectomy:
  
  • consider for pts with PTH > 800pg/mL
    
    • need to monitor Ca2+ closely after procedure
    • IV Ca2+ may be needed then PO vitamin D + Calcium

Question 22

Vitamin D

Answer 22

• acts direction on parathyroid gland → reduces PTH level
  
  • when to use: reduction of phos levels does not reduce PTH level enough
• 3 forms of Vitamin D:
  
  • ergocalciferol (vitamin D2, lowers PTH for stage 3 CKD)
  • cholecalciferol (vitamin D3, lowers PTH in stage 3 CKD)
  • Calcitriol: (1,25-dihydroxyvitamin D) = MOST ACTIVE
    
    • good for CKD stage 4-5
      
      • because kidneys cant produce 1-alpha-hydroxylase (which normally converts D2 and D3 to active form)

Question 23

Types of Vitamin D

Answer 23

• Vitamin D precursor
  
  • ergocalciferol (Vitamin D2)
  • Cholecalciferol (vitamin D3)
• Active Vitamin D
  
  • Calcitriol
• Vitamin D analogs
  
  • Paricalcitol
  • Doxercalciferol
• Calcimimetics
  
  • Cinacalcet

Question 24

Familial hypocalciuric hypercalcemia

Answer 24

Autosomal Dominant

• loss of function mutations in the (CaSR) gene in the parathyroid gland increases the set point for calcium sensing. It makes the parathyroid glands less sensitive to calcium, and a higher than normal serum calcium level is required to reduce PTH release
• generally asymptomatic genetic disorder of phosphocalcic metabolism characterized by lifelong moderate hypercalcemia along with normo- or hypocalciuria and elevated plasma parathyroid hormone (PTH) concentration

Question 25

What is osteomalacia?

Answer 25

**Osteomalacia** is a condition of decreased bone density due to **defective mineralization**.