Gosmanov Flashcards

Question

What are the PTH-dependent causes of hypercalcemia?

Answer 1

- Primary hyperparathyroidism: main cause 1. Tertiary hyperparathyroidism - Familial hypocalciuric hypercalcemia (FHH) - Medication-induced: Lithium of HCTZ-mediated -\> looks just like primary, but pt. will be on one of these meds

Answer 2

- Tumor-induced: PTHrP or bone metastases - _Granulomatous diseases_ (TB, sarcoid, lymphoma): ↑ 1,25 vit.D 1. Activation of local 1-alpha-hydroxylase, INC expression of Ca transporters in the intestine - _Multiple myeloma_ - Hyperthyroidism/adrenal failure: osteoclastic activity of the thyroid hormones - Immobilization: rapid bone turnover -\> may be seen after spinal cord injury or long bone fracture in children and adolescents - _Medication-induced_: vitamin D toxicity, vitamin A toxicity, milk-alkali syndrome

Answer 3

- 80-85% adenoma - 15% hyperplasia -\> MEN1, MEN2A, HPT- jaw tumor syndrome, familial HPT - \<1% parathyroid carcinoma

Answer 4

- _Risk factors_: age, race (AA \> W \> H), sex (F \> M) 1. Almost 3x as common in women than men - Etiology unknown (adenoma, hyperplasia) - _Clinical features_: serendipity 1. Stones 2. Abdominal moans 3. Psychic groans 4. Bones

Answer 5

- Symptoms are non-specific, and _majority of patients are asymptomatic_ - Fatigue/weakness, musculoskeletal pain, pruritis - Polydipsia/polyuria, renal failure/kidney stones - Constipation, anorexia/nausea/dyspepsia, pancreatitis - Depression/memory loss - Osteoporosis/fracture, HTN

Answer 6

- BIOCHEMICAL: 1. Ca, albumin (ionized Ca) 2. PTH 3. 25-OH Vitamin D 4. 24-hr urine Ca to differentiate from FHH -\> no interventions recommended in FHH, but just observe them a. Urine Ca in pts w/1^o hyperPTH normal or slightly elevated; very important for milder cases to collect the 24-hour urine Ca - IMAGING: make biochem dx first, then do imaging 1. Thyroid US, ⁹⁹Tc-sestamibi scan: localization studies to help surgeon know where to go (minimally invasive) 2. DXA: bone scan

Answer 7

- One criteria suffices for parathyroidectomy: 1. Ca \> 1.0mg/dL above upper limit of normal 2. Age \<50 3. Osteoporosis 4. Renal insufficiency

Answer 8

- Adequate hydration - Bisphosphonates in pts with osteoporosis - Maintenance of Vit D status (20-30ng/mL) - Cincalcet: calcimimetic that activates CaSR in PTH gland -\> for those who do NOT qualify for sx, and have moderate hypercalcemia (Ca \>12.5mg/dL) - _Annual follow-up_: Ca/PTH, renal function, DXA

Answer 9

- Familial hypocalciuric hypocalcemia: 1. Inactivating _mutation of CaSR_, 100% penetrance: need a higher Ca to shut down PTH production a. Also have _lesions in kidneys_, impairing Ca excretion 2. Mildly elevated serum Ca, high-normal/mildly elevated PTH, hypocalciuria 3. ASYMPTOMATIC 4. Work-up: serum Ca, PTH, 24-hr urine Ca (\<50-100mg/24-hr), can also ask relatives to check serum Ca, genetic testing 5. NO TX is indicated - _Note_: some pts early in primary hyperPTH will present in a similar manner (normal PTH, and mildly elevated Ca)

Answer 10

- Occurs in the face of _long-standing 2^o hyperPTH_ - Parathyroid glands develop hyperplasia due to chronic low calcium and/or high phosphorous levels - At one point, these _glands become autonomous_ (recall Primary HPT) 1. In the setting of end-stage renal disease 2. Post-kidney transplant

Answer 11

- _Etiology_: breast, lung, lymphoma, thyroid, kidney, prostate, multiple myeloma, pancreas, etc. 1. Most common: breast, squamous cell carcinoma - PTH LEVEL WILL BE SUPPRESSED (bc PTHrp binds to the same receptor -\> INC IC cAMP) - _Clinical presentation_: consistent w/signs and sxs of hypercalcemia and potential diagnosis of malignancy 1. Polyuria, dehydration, confusion, abdominal and musculoskeletal pains, fatigue, N/V 2. Weight loss, pulm symptoms, LAD, history of cancer, anemia, abnormal chest X-ray

Answer 12

- Bony metastases can increase calcium levels - Humoral factors (cytokines, TNFa) can activate osteoclasts - Multiple myeloma can cause significant bone destruction resulting in hypercalcemia

Answer 13

- NORMAL SALINE INFUSION - Signs of dehydration: LOW BP, high HR, and high creatinine, suggesting kidney injury 1. Need to maintain vol to keep this patient alive - Hypercalcemia can cause _polyuria and dehydration_ - _Calcitonin_ injections are 2nd or 3rd line therapy (will kick in within 24 hours) - _Diuretic therapy_ only in pts that still have high calcium after volume repletion

Answer 14

- Address volume status: normal saline - Saline Diuresis ± Furosemide: \*only after volume status is corrected - Calcitonin: 3-4 days - Bisphosphonates: Pamidronate IV - works for 2-3 wks or Zoledronic acid IV - works for 1-3 months - Glucocorticoids: \*useful in myeloma, granulomatous disease, vitamin D toxicity -\> DEC activity of 1-alpha-hydroxylase - Dialysis

Answer 15

- Hypocalcemia - Hyperphosphatemia - Vitamin D deficiency

Answer 16

- Takes time for the other glands to “wake up” after parathyroidectomy

Answer 17

- Symptoms non-specific and likely related to underlying disease causing elevated PTH, but not due to PTH itself - Evaluate key elements of the Ca axis: serum PTH, Ca (with albumin), Phosphorous, Creatinine, Vit D 1. Do NOT collect 24-hour urine for calcium - No indications for imaging studies if Ca is normal - Treat underlying reason(s), and make sure Vit. D is always replete

Answer 18

- Severe Vit. D deficiency is rare - Presenting complaints in mild-to-mod Vit. D def are very non-specific: musculoskeletal pains, fatigue - 50% of pts with osteoporosis have vit. D deficiency - _Vitamin D replacement_ (\>800 units/day) showed ~20% reduction in risk of fractures 1. Benefits of Vit. D replacement for prevention of cancer, DM, infections, HTN controversial 2. J-shape association between mortality and vitamin D levels

Answer 19

- Agitation - Hyperreflexia - Convulsions - HTN - Long QT - Trousseau's sign (BP cuff); Chvostek's sign (facial N)

Answer 20

- HypoPTH: 1^oprocess as low PTH DEC Ca 1. Post-thyroidectomy 2. Idiopathic: Abs to PTH 3. Autoimmune 4. Parathyroid agenesis, e.g., DiGeorge 5. HypoMg, hyperMg, hypophosphatemia - HyperPTH: 2^o process (PTH INC due to low Ca from other causes) 1. Renal failure 2. Vit D deficiency 3. Vit D or PTH resistance syndromes

Answer 21

- Acute _pancreatitis_: free fatty acids chelate calcium - Massive _transfusion_: infusion of citrate will complex with calcium leading to decreased ionized calcium - _Tumor lysis syndrome_ or rhabdomyolysis: phosphate release binds to ionized calcium - Severe _sepsis_: Cytokine-mediated - Medications: phosphate, _bisphosphonates_ - Hungry bone syndrome

Answer 22

- H&P - Check albumin and total Ca x 2 - Check PTH 1. Low PTH: a. Hypoparathyroidism b. Magnesium deficiency c. Phosphate excess 2. High PTH: a. Severe Vit. D deficiency b. Renal failure c. Vit. D or PTH resistance

Answer 23

- Idiopathic _inherited forms of PTH resistance_ - Elevated PTH (1000s), hypoCa, hyperphosphatemia and/or specific morphological features including: 1. Short stature, rounded face, foreshortened 4th and other metacarpals, obesity (_Albright`s Hereditary Osteodystrophy_- AHO) - Molecular defect - inability of PTH stimulate IC signaling events (cAMP pathway) due to **mut in Gsa** subunit or elements downstream to cAMP signaling - Variability in AHO and PTH renal resistance, so the condition is subclassified

Answer 24

- Acute Hypocalcemic Crisis: 1. Always **correct magnesium** if low (responsible for PTH production) 2. Calcium Gluconate: 1-2 ampules over ~10-20 minutes, followed by infusion, if indicated - Long-term Management: 1. Oral Calcium salts 2. _Vitamin D_ a. Ergocalciferol/Cholecalciferol (act in 10-14 days) -\> effective only if PTH is present b. Calcitriol – active vitamin D 3. _Hydrochlorothiazide_: INC reabsorption of Ca in the distal tubule

Answer 25

- Magnesium - This will help PTH go up, then Ca and phosphorous levels will correct - Obviously, this is an extreme hypothetical (I'm sure fixing K+ would be more important)

Answer 26

PRIMARY hyperPTH

Answer 27

- _Multiple endocrine neoplasia_: syndrome in which 2 or more endocrine tumors occur in a single patient 1. Auto dominant (e.g., DNA deletion): germline or sporadic mutations (2nd hit hypothesis) 2. Different penetrance (varying phenotype) 3. Benign and malignant 4. Functionally active and inactive

Answer 28

- Parathyroidectomy improves hypercalcemia, and reduces gastrin

Answer 29

- Hypercalcemia due to **1^o HPT** by age 40 (19-40): most likely to present with this - Pituitary tumors dx on average at age 38 (12-83) - Pancreatic tumors: 1. Insulinoma at age 25 2. Gastrinoma at age 35

Answer 30

- Affected gene - Presentation/penetrance - Signs/symptoms - Screening - Therapy

Answer 31

- Some of the clinical features of MEN2B - Mucosal neuromas - Marfanoid habitus

Answer 32

- _Cortical bone_: outer, dense shell -\> about 80% of total skeletal mass - _Trabecular bone_: network of connecting plates inside the cortical shell -\> about 20%

Answer 33

- Dense outer shell of compact bone; defines bone shape -\> 80% of skeletal mass - Essential functions 1. Provides biomechanical strength 2. Attachment site for tendon and muscle 3. Protection against excess trauma - Turnover rate of 2-3% per year

Answer 34

Cortical bone thinning and INC porosity -\> INC significantly with age

Answer 35

- A sponge-like network of delicate plates of bone known as trabeculae -\> 20% of skeletal mass - Essential functions: 1. Mineral metabolism 2. Strength and elasticity - Higher turnover rate compared to cortical bone

Answer 36

Resorption pits from osteoclasts

Answer 37

- RANK: Receptor activator of NFkB 1. Expressed by osteoclasts and their precursors - RANKL = RANK Ligand (paracrine effect) 1. Expressed by osteoblast/stromal cells 2. Promotes osteoclast differentiation, maturation, and prolongation of lifespan through RANK - OPG: Osteoprotegerin 1. Secreted by osteoblast/stromal cells “Decoy” receptor for RANK 2. Blocks RANKL signaling

Answer 38

- BONE FORMATION: 1. Bone-specific alkaline phosphatase 2. Osteocalcin 3. Carboxyterminal _propeptide_ of type I collagen (P1NP) - BONE RESORPTION: 1. N-telopeptide 2. Carboxyterminal of type I collagen (CTX-1)

Answer 39

- Skeletal disorder characterized by compromised bone strength predisposing to an INC risk of fracture - Bone strength primarily reflects the integration of bone density and bone quality -\> _less bone mass and bone quality_ in osteoporosis - We have tools to determine bone mass, but not really bone quality. - **Bone resorption \>\>\>\> bone formation**

Answer 40

- **Genetics** is very important: 75% of our bone mass is genetically predisposed; other 25% is diet and exercise - Accrual of bone density occurs in teens and young adulthood - _Balance_: age, meds can affect this -\> fall prevention is very important for pts with osteoporosis - Marginal benefits seen with _hip protectors, soft tissue padding_ (for big bone fractures; risk for small, distal fractures)

Answer 41

- Calcium - Phosphorous - DXA - 25-OH Vitamin D: 1/2 life of active Vit D is so short, so 25-OH Vit D measured - **Do work-up sequentially** —\> Ca first, then PTH measurement (i.e., only if the Ca is high)

Answer 42

- Central **DXA** (dual energy x-ray absorptiometry): gold standard to measure bone mineral density - BMD is an _important predictor of fractures_ - Very low level of radiation exposure, and no side effects

Answer 43

- DEC BMD = INC fracture risk - Each S.D. decrease corresponds to roughly a doubling of fracture risk - For a T-score of -2 there is a 4x risk of fracture and so on

Answer 44

- T-score equal or less than -2.5 is diagnostic of osteoporosis 1. Low-trauma fracture when T-score is more than -2.5 is also consistent with osteoporosis - Cost-effective to initiate treatment in these patients; we call these pts osteoporotic -\> **REMEMBER THIS** - If you break a bone in a non-traumatic way, no matter what your bone density is, it is still osteoporosis -\> if pt has osteopenic bone density range, but gets a non-traumatic fracture (fall from the same height), this is **STILL OSTEOPOROSIS** 1. This is also true even if at -0.5; bone density measurements are not perfect

Answer 45

- Bone breaking when coughing or sneezing, or breaking back when changing tire - Can be related to metastatic process into the bones

Answer 46

- To diagnose osteoporosis - To decide when to start treatment - To monitor response to treatment

Answer 47

- Age predisposes to fracture risk - Bone density picks up something important, but cannot describe all of the processes that are happening in bone

Answer 48

- Glucocorticoids - Long-acting benzodiazepines: anti-anxiety - Tricyclic antidepressants and antipsychotics - PPIs - SSRIs - Anticonvulsants (long- term therapy) - Aromatase inhibitors - Androgen deprivation therapy

Answer 49

- Femoral neck T-score - Age - Previous low trauma fracture - Low BMI - Current cigarette smoking -\> do NOT use any tobacco - High alcohol intake: more frequent falls, and hypogonadal (low testosterone and estradiol) 1. Estradiol activates osteoblasts, and INH osteoclasts; any condition that affects testosterone levels can affect bones -\> only 3 drinks and above is detrimental to your health - Steroid use - Rheumatoid arthritis - Family history of fracture: 75% of bone genetically determined - FRAX (online) tool used to identify pts with high enough risk for tx

Answer 50

- Chronic steroid use -\> Cushing`s syndrome - Obesity, accelerated weight gain, buffalo hump -\> Cushing`s syndrome or disease - Hypercalcemia -\> primary hyperparathyroidism or malignancy-mediated - Arthralgias, large hands and feet, obstructive sleep apnea -\> acromegaly - Kidney stones -\> secondary hyperparathyroidism from hypercalciuria - Low libido, erectile dysfunction, loss of muscle mass -\> hypogonadism - Suppressed TSH -\> hyperthyroidism (also associated with osteoporosis) - Idiopathic or post-menopausal osteoporosis is always a diagnosis of exclusion

Answer 51

- Optimize lifestyle: 1. Stop tobacco/ETOH 2. INC physical activity 3. Adequate Ca: 1200mg/d 4. Optimize Vit. D. level: \>30mg/dL 5. Fall prevention - Pharmacological therapy: 1. Antiresorptive agents 2. Anabolic agents: help to build up new bone

Answer 52

- T-score \<=(-)2.5 after age 50 - Treat osteopenia with history of fragility fracture - Use FRAX score to decide who to treat of those younger than 50 with a T-score \<=(-)2.5 or older than 50 with a T-score \>=(-)2.5 - 10-yr risk of \>3% for hip fracture, or \>20% for major osteoporotic fracture is sufficient to initiate pharma treatment

Answer 53

- Osteomalacia/Ricketts - Paget disease of bone - Osteopetrosis - Osteogenesis imperfecta - Osteitis fibrosa cystica - Fibrous dysplasia

Answer 54

25-OH-D₂ ## Footnote - Low serum phosphorous, low serum Ca, low FGF23, and high PTH favor production of 1,25-OH-D₃

Answer 55

- Failure of mineralization: defect in inorganic component of bone or _inadequate mineralization_ of the bone matrix 􏰄- Osteomalacia is softening of adult bone, and rickets is softening of growing bone 1. Osteomalacia: low phosphorous & low Vit D - Most comm cause of defect in bone mineralization is _severe vitamin D deficiency_ (via nutrition, lack of sunlight, or liver disease) 1. Hypovitaminosis D —\> suspect when **below 5-10ng/mL**: Ca transport in gut stimulated by Vit D \>10ng/mL, but not really when below that

Answer 56

- Type I Vitamin D Dependent Rickets 1. Autosomal recessive 2. **Defect in activity of 1 alpha-hydroxylase** (very low levels of 1,25 (OH) D) - Type II Vitamin D Dependent Rickets 1. Autosomal recessive 2. **Defect in receptor response to 1,25 dihydroxyvitamin D** (high circulating levels of 1,25 (OH) D)

Answer 57

- Excessive bone resorption followed by excessive bone formation -\> excess # of osteoclasts with more nuclei than usual 1. Osteoblasts are in excess but morphologically normal - Bone formed is not normal; there is too much bone of poor quality -\> enlarged skull, deformities in extremities, bony pains 1. Complications: fxs, hearing loss, bone tumors - Image: cortical thickening, expansion, and mixed areas of lucency and sclerosis (contrasted with normal bone in the proximal half)

Answer 58

- Increased Bone Specific Alkaline Phosphatase (CMP) - Usually measure total serum Alkaline Phosphatase so routine lab work will show increase in the total enzyme level - Ca, phosphorous, Vit D, and renal function should be normal (you check these to rule out other causes)

Answer 59

- **Too much bone, but of poor quality** - Laboratory studies are usually normal and DXA shows very high (positive) bone mineral density (BMD) values - Fractures can occur in spite of high BMD: have negative T-scores

Answer 60

- Low levels of type I collagen synthesis by fibroblasts, and mutations within the pro-alpha1 and pro-alpha 2 type I collagen genes - Heritable disorder - Patients have: 1) skeletal pains, 2) recurrent fractures, 3) skeletal deformities - Blue sclera in some cases

Answer 61

- Bone disease of **hyperparathyroidism**: high bone turnover state - _Epi_: can be seen in 1^o hyperparathyroidism and ESRD pts w/very high PTH levels -\> now in **\<10% of pts** bc early dx of conditions with elevated PTH - _Histo_: INC in # of bone-resorbing osteoclasts, marrow fibrosis, and cystic lesions that may contain fibrous tissue (**brown tumors**) - _Clinical_: bone pain and sometimes pathologic fractures -\> osteoporosis due to preferential loss of cortical bone - _Radiology_: most sensitive and specific finding is subperiosteal resorption of cortical bone, best seen in high-resolution films of the phalanges (bones of hands and feet); similar process in the skull leads to a salt-and-pepper appearance (see attached images) 1. Bone cysts or brown tumors may present as osteolytic lesions - _Labs_: elevated PTH, elevated Ca in primary HPT and normal or low-normal Ca in ESRD; elevated markers of bone turnover, incl alkaline phosphatase

Answer 62

- Sporadic disorder w/1 (monostotic) or more (polyostotic) expanding fibrous skeletal lesions of bone-forming mesenchyme -\> do NOT differentiate into osteoblasts, so **imperfect bone** 1. Fibroblast-like cells w/features of osteoblasts in some areas -\> produce ECM that organizes into woven bone - **NOT hereditary** -\> exact mechanism unknown - Polyostotic form assoc w/cafe au lait spots and hyperfunction of endocrine system as pseudo-precocious puberty of ovarian origin is known as **McCune-Albright syndrome** (MAS) - Molecular defect: **activating muts in GNAS1** gene that encodes α subunit of stimulatory G protein (Gsα) - Postzygotic muts in early devo, but variable, explaining **mosaic pattern of skin/bone changes** -\> muts of GsαPCR may cause autonomous function in: 1. Bone (PTH hormone receptor) 2. Skin (MSH receptor) 2. Various endocrine glands, incl ovary (FSH receptor), thyroid (TSH receptor), adrenal (ACTH receptor), and pituitary (GHRH receptor)

Answer 63

- _Monostotic form_ most common, and dx in pts bt **20-30-y/o** w/o assoc skin lesions - _Polyostotic form_ in kids **\<10-y/o**, and may progress w/age -\> lesions most comm involve maxilla, o/craniofacial bones, ribs, and metaphyseal or diaphyseal portions of the proximal femur or tibia 􏰇- _Symptoms_: expanding bone lesions may cause **pain, deformity, fractures, and nerve entrapment** 􏰇- _Signs_: may have **café au lait spots** (flat, hyper-pigmented skin lesions w/rough borders), most common endocrinopathy is isosexual **pseudo-precocious puberty** in girls 1. Other, less common endocrine disorders incl thyrotoxicosis, Cushing’s, acromegaly, hyperparathyroidism, hyperprolactinemia - _Labs_: **hypophosphatemia** may be due to FGF-23 made by abnormal fibrous tissue; Ca, PTH, Vit D are normal, markers of bone turnover can be elevated 􏰇- _Radiology_: well-defined fibrous dysplastic lesions in long bones -\> **radiolucent areas** with thin cortices and a ground-glass appearance (may be lobulated with trabeculated areas of radiolucency)