How is serum ionized and total calcium influenced by Albumin and pH? Describe the trends
Albumin - binds Ca and is part of total Calcium measured
- low albumin state lowers the Total but not the ionized calcium
pH changes are like so:
- Alkaloses lowers ionized Ca and increases protein-bound calcium vs Acidosis rasises Ionized Calcium and lowers protein-bound calcium
CC: Hyperventilation causes respiratory alkalosis and reduces ionized calcium giving people the tingling sensation!
How do you measure ionized calcium? How do you estimate ionized calcium from total calcium?
Measuring ionized calcium is hard....samples taken careully and directly to freezer - finicky test and sucks to do.....SO INSTEAD....
Estimate Ionized Ca from Total Calcium and Albumin concentration!
CORRECTION FACTOR = (4-Albumin) x 0.8
Add correction factor to Total Calcium to get corrected calcium
*Corrected for low albumin
What are the most important organs and hormones in calcium regulation?
Organs - intestines, bones, kidneys
Hormones - PTH and Calcitriol
What is the relationship between PTH secretion and Calcium levels? What regulates this? Describe the relationship graphically.
Calcium sensing receptors on the Parathyroid cells act as the Calciostat and sense Ca in serum and either raise or lower PTH levels accordingly
More Calcium then PTH down
Less Calcium PTH up
(see graph picture)
Walk through the process of Vitamin D production and regulation.
1) 7-dehydrocholesterol in skin + UBV sunlight --> Vitamin D3
2) Vitamin D3 to the liver --> 25-OHD3
3) 25-OHD3 to the kidney --> 1,25OH-D3 aka Calcitriol which is the active form
Vitamin D2 from exogenous plant sources undergoes same 25 and 1-hydroxylation as D3
- 7-dehydrocholesterol in skin decreases w/ age so need more sun and Melanin absorbs UVB more so darker pigments need more sunlight
- 25-OD D is what you measure to Dx Vitamin D deficiency
- 1-Hydroxylation in kdiney regulated and INCREASED by PTH but that ability decreases w/ age and renal insufficiency
How does PTH act on it's target organs?
- Acute exposure stimulates bone formation by osteoblasts BUT prolonged exposure stimulates bone breakdown by osteoclasts (*can use synthetic PTH for osteoporosis)
GI Tract: no direct effect
- PTH promotes Ca absorption and P excretion in the proximal tubule
- stimulates 1-hydroxylase production
What is the difference in renal effects from PTH vs 1,25D?
PTH tells kidney to lose P and hold onto Ca
1,25 D tells kidney to hold onto BOTH Ca and P!!!
What is the mechanism of different actions of PTH on bone cells? (RANK-RANKL expression pathway)
PTH binds receptors on OB acutely to stimulate them --> bone formation AND expression of RANKL cell surface receptors
then OC Precursors w/ RANK on their surface bind w/ RANKL and causes them to differentiate and activate into mature OC and get bone destruction
Vitamin D 1,25 actions on Target Organs?
- stimulates bone breakdown at high levels and maintains serum Ca and P for bone formation
Ca and P absorption increased
- inhibits PTH release - feedback control!
What is Calcitonin? Actions? Where does it come from?
Calcitonin releaased and made by Thyroid C Cells
does NOT play a role in NORMAL physiology
pharmacologic doses inhibit bone resporption
What is PTHrP? What is the physiologic role and pathologic role?
Parathyroid Hormone Related Peptide (aa2-13) bids to the same receptor as PTH
Made in Fetal parathyroid, cartilage, keratinocytes, placenta and in adult breast
Used for mobilization of Ca in pregnancy to make baby bones and for lactation
causes Hypercalcemia in Solid tumors!!!!!!
Where is phosphorous found? REgulated by? Too much causes? relation to 1,25 D?
Phosphorous is a major component of Hydroxyapatite and cell membranes and ATP etc
Too much phosphorous can cause Vascular Calcification and therefore is tightly controlled
PTH and FGF23 (made by Osteocytes) stimulated by increased P and leads to Phosphaturia
*PTH stimulates 125D and FGF23 inhibits it!
What is the most common cause of Outpatient Hypercalcemia?
What are the causes of Primary Hyperparathyroidism?
85% Single adenoma
10% hyperplasia - sporadic or MEN1/2, or hereditary jaw tumor hyperparathyroidism sundrome
5% Ectopic - neck/mediastinum
Signs and Symptoms of Hyperparathyroidism?
Range from none to life-threatening depending on Degree of elevation of Ionized CA (>12 mg/dl; normal 8.5-10.5)
Bones - osteoporosis and fracture and pain
Stones - polyuria, azotemia, stones
Moans - NM weakness, fatigue and joint pain
Groans - GI constipation, anorexia, vomiting
Psychological Overtones - CNS - depression to obtundation
Other - eye Band Keratopathy
NARROW QT --> how people die from cancer from high PTrP
What causes Autosomal Dominant Primary Hyperparathyroidism? What are the different types/forms of disease (MEN)? Which one causes Hypercalcemia?
Multiple Endocrine Neuromas!!!
MEN1: Parathyroid, Pituitary, Pancreas
- Increased Calcium!!!!!!
-Menin gene inactivation (tumor suppressor)
MEN2a: C Cells, Adrenal, Parathyroid
- Thyroid tumor
-ret gene activation (proto-oncogene)
MEN2b: C cells, Adrenal, Nerves, Parathyroid
- Thyroid tumor
- Ret gene activation
What are markers / how do you diagnose Primary Hyperparathyroidism? What else can also be associated with this?
Elevated Serum Ca
Elevated or inappropriately normal iPTH (should be suppressed)
Elevated or normal Urine Calcium (not low)
- elevated Calcitriol
-low normal/low serum phosphorous
-Mild hyperchloremic Metabolic Acidosis
How do you treat Primary Hyperparathyroidism? Surgical or Medical?
Asymptomatic - observation
Symptomatic = Surgery w/ Sestamibi scan
if US+ - minimally invasive
if US- then 4 gland exploration
If poor surgical candidate treat medically w/ Cinacalcet which is Calcium Sensing Receptor Antagonist and tells Parathyroid gland to not release PTH
What is Familial Hypocalciuric Hypercalcemia?
AD mutation that's rare
Inactivating mutation on the Calcium sensing receptor so always thinks not enough Ca/PTH and so keeps releasing PTH
Shifts PTH / Ca Curve to the Right
Kidney effects - Uca low and increase reabsorption of Ca
Diagnosed by low Ca/Cr clearance ratio
does NOT require treatment
What are potential causes of non-PTH mediated hypercalcemia? What lab values would you see?
Here, PTH suppressed in response to High Calcium indicating normal Parathyroid feedback response
3 types of causes:
1) 1,25 OH D mediated: Vitamin D intoxication, Granulomatous diseases, Lymphomas
2) PTHrP Mediated - Cancer
3) Other - Milk Alkali syndrome or Multiple Myeloma
What is the most common cause of inpatient (symptomatic) Hypercalcemia?
CANCER - PTHRP MEDIATED!!!
How do you treat Hypercalcemia overall? Acutely?
Overall: Treat Underlying cause:
- Primary hyperparathyroid - surgery
-cancer - surgery, CTX/RTX
-granulomatous disease - glucocorticoids
ACUTE TREATMENT WHILE WAITING FOR DX:
- Saline and Loop Diuretics (Furosemide)
-IV Bisphosphonates - best is Zoledronic Acid (also used in osteoporosis)
- Calcitonin - minimally effective
How do IV bisphosphonates work?
Used for Acute tx of Hypercalcemia and for Osteoporosis
They have a phosphate moiety that is P-O-P and so binds to bone and OC can not break bone down --> REDUCE TURNOVER so can't get more Ca out of bones
What is the presentation and what are the causes for secondary Hyperparathyroidism?
Nothing wrong w/ Parathyroid glands but they are reacting properly to something else
DX: Normal or Low Calcium and Elevated PTH
- Whole body deficiency of Ca or Excess P
Most common Cuase is CKD!!!!
- Hypercalcuria - renal tubular leak
What are complications of Secondary Hyperparathyroidism?
Bone loss from PTH breakdown
If associated w/ increased serum P like in CKD then Vascular Calfications
How does Tertiary Hyperparathyroidism arise? How do you diagnose it?
Diagnosis - elevated Ca and Elevated PTH or inappropriately normal PTH (same as Primary)
Follows previous secondary hyperparathyroidism - CKD
Pathology cahgnes from Hyperplasia to development of Monoclonal Tumor (adenoma) w/ Autonomy
What are the markers / how do you diagnose Hypoparathyroidism?
Low serum Ca
LOW PTH or inappropriatly normal PTH (should be high)
What are the etiologies of Hypoparathyroidism?
Post-operative - Thyroidectomy, Head/Neck surgery MOST COMMON!
Autoimmune - Polyglandular failure syndrome - AIRE gene
Autosomal Dominant - CASR Mutation - 50%
(vs FHH where inactivating mutation here it is the opposite and overly stimulated so stop releasing PTH and shift curve LEft)
What are the signs and symptoms of Hypocalcemia?
TETANY!!!! HALLMARK - paresthesias, cramps, laryngospasm
Chvostek Sign and Trousseau Sign
Mental status - fatigue, anxiety, depression --> Psychosis
Head - Calfication of basal ganglia and papilledema
CV - Prolonged QT and Heart failure
Cataracts in Eyes
Fetal - dental hypoplasia
Kidney - stones and nephrocalcinosis - from small group - can get these in both hypo and hyper
What is Chvostek sign?
What is Trousseau Sign?
Chvostek - tap along facial nerve and see ipsilateral twitching
Trousseau - elevated BP cuff over systolic for 2 minutes and see carpal spasm
What is Pseudohypoparathyroidism? What is the clinical Presentation?
Resistance to PTH
Albright's Hereditary Osteodystrophy
End organ resistance to PTH
See Low serum Ca, Elevated P and PTH
- short stature
- short pinky and ring fingers
- Wide spaced nipples (teee hee)
How do you diagnose and what are some causes of Vitamin D Deficiency? Cutoff for deficiency?
Diagnose: Normal Calcium and Phosphorous but LOW 25-OH-D
TEst 25 OHD!!!!
- inadequate sun (+old age) or malabsorption like in IBD
- Anticonvulsants increase Vit D catabolis
-Obesity - D sequestered in fat
CUTOFF: 25-OH-D < 30!!!
What are symptoms of Vitamin D deficiency in kids and adults?
Childhood - bones are soft --> Rickets
- Bowed long bones
- Rachitic Rosary
Adults - Softening of bones --> Pseudofracture
"looser's Zones" = indentation where arteries course over bones
What can cause / what do you see in Vitamin D resistance?
Hereditary Vit D Dependent Rickets:
HVDDR Type 1 - Lack of 1-Alpha Hydroxylase
Responds to Tx w/ 1,25 OHD2
HVDDR Type 2 - mutations in Vit D receptor and TRUE RESISTANCE
-associated w/ ALOPECIA!!! NO HAIR ANYWHERE!
Treatment of hypocalcemia?
both mild and crisis?
Mild Hypocalcemia - oral calcium and Vitamin D
Crisis - symptoms include tetany, laryngospasm, seizures
Treatment - IV Ca infusion and Calcitriol
Describe releationship between bone mass and strength and age. How can you get Osteoporosis?
Bone Mass is proportional to bone strength and fracture risk
Peak Bone mass in early 20s (F) and mid 20s (M)
>80% controlled by genes
Osteoporosis - from failure to attain normal Peak bone mass or from bone loss or both!
What are the 2 Monogenic (developmental) Bone disorders?
Osteoporosis Pseudoglioma Syndrome (OPPG) from lack of signal transduction
- Inactivating mutation in LRP5 (LDL-Receptor-like-protein-5) so less bone is produced
-Childhood Osteoporosis and Congenital Blindness
Osteogenesis Imperfecta - defect in Excracellular proteins
- mutations in Type 1 Collagen genes
- Osteoporosis +/- Blue Sclerae
What are RF for osteoporosis?
White or Asian
Low body weight - especially post-menopausal women
Alcohol use (EtOH toxic to osteoblsats)
Hypogonadism (up to 1/3 men)
POor calcium intake
What are some secondary causes of Osteoporosis to be aware of?
- Glucocorticoids like prednison
- Aromatase Inhibitors
- Chronic Anticoagulants
- Antidepressants and Anti-convulsants
-DM 1 and 2
- GI problems - Celiac's Crohns, UC
-Chronic illness - COPD, CHF
- Muscle weakness
How do you diagnose Osteoporosis? Osteopenia vs osteoporosis?
HIP FRACTURE OR SPINE COMPRESSION FRACTURE
OR by DXA which measure Bone mineral density
Use T score for post-menopausal women and men >50 yo:
Osteopenia - T score -1.0 to -2.5
For every -1 on T score, RR of fracture increases 2-3 fold
Use Z score for children and young adults:
SD from age matched controls and Fragility Fracture
Who gets treated in osteoporosis?
EVERYONE GETS TREATED!!!! who has osteoporosis
Osteopenia - calculate absoulte 10 year risk of fracture w/ FRAX tool and treat those w/ >20% risk for fracture and/or anyone w/ fracture of hip or >3% risk fracture of hip
What are the different types of treatments for OSteoporosis?
Anti-resorptive --> Interfere w/ OC function
- Bisphoshphonates: Alendronate, Risendronate, Zolendronc Acid, or Ibandronate (Ibandronate does not reduce hip fracture)
RANKL Inhibitor- Denosumab
SERM - Reloxifene
Calcitonin - Treat Hypercalcemi
Anabolic --> Get OB to build bone
- Teriparatide PTH 1-34 SubQ injections
- CA and Vit D (best to give 25OHD really high doses)
-exercise and weight bearing improved BMD
What is PAget Disease of Bone? Who gets it? How does it work?
Osteoporosis is global whereas Paget Disease is Focal disorder of bone metabolism
See areas of enlarged but weakened bones and can cause bone pain and neurological complications
2-3% 40 yo but >80 yo 10% prevalence
Pathophysiology: Increased rate of bone turnover via increased # OB, OC, and vasculature leading to new, immature, fragile woven bone that is prone to fracture
What are the clinical features of PAget Disease?
- Increased warmth over bone bc more vasculature
- fracture bone deformity
- HF and/ or neurological
-Rare - OSTEOSARCOMA!
What bones are affected in PAget's Disease?
2/3 polyostotoic and 1/3 monostotic
ANY bone can be affected - doesn't spread to new bones over time!!!
Most common bones:
72% Pelvis, then Spine, Skull, Tibia
What are Lab markers of bone formation? Bone Resporption? Turnover?
What do you see in PAgets?
Bone Formation = Alkaline Phosphatase (osteocalcin)
Bone Resorption Marker = N-Telopeptide (morning urine) or serum C-Telopeptide, Urine Pyridinium crosslinks, Hydroxyproine
Markers of bone Turnover - correlate w/ eachother and disease severity
In PAgets -- BOTH ELEVATED!!!
What do you see on RAdiographic evaluation of Paget's Disease?
can get nuclear bone scan or XR and see areas up uptake
use MRI or CT to rule out tumor (+/-Biopsy)
Osteoporosis Circumscirpta - one little punched out area
Picture Frame Sign - vertebrae getting bigger but more luscent inside
Pelvic Brim sign - coarsening trabeculae
Cotton Wool Spots - snowstorm appearance
Treatment for PAget's Disease?
Treat ALL patients w/ Bisphosphonates to reduce bone turnover bc natural history of disease is progression and want to prevent fractures
What is Renal Osteodystrophy? Who gets it and why?
What are the types?
Present in ALL pts w/ CKD by the time that they reach dialysis due to 1) Phosphate Retention 2) Excess PTH and 3) reduced Production of 1,25 OH-D
Hyperparathyroid Bone Disease - Osteitis Fibrosa cYstica - HIGH PTH!!!!
Adynamic Bone disease - lower than expected PTH
Mixed - Osteomalacia and Hyperparathyroid
What are Hereditary Rickets Diseases? Name them - 3 - and their presentation/features?
Rickets and Osteomalacia due to Hypophosphatemia: Renal Phosphate Wasting:
XLH: X-linked Hypophosphatemic Rickets
Fanconi Syndrome - renal wasting of P, glucose, AA, and associated w/ renal failure
- Phosphate and glucose and AA wasted
Oncogenic Osteomalacia (FGF23) - benign mesenchymal tumor produces FGF23
- Phosphaturia --> Osteomalacia and fractures