10/12- Diseases of Mineral Metabolism Flashcards
1
Q
What are the 3 main bone minerals?
- Hormones involved?
- Organs involved?
A
Minerals:
- Ca
- Phosphate
- Mg
Hormones:
- PTH
- 1,25(OH)VitD3
- Aka 1,25 dihydroxycholecalciferol - Calcitonin
Organs:
- Intestine
- Kidney
- Bone
2
Q
How is serum calcium distributed (what forms)
A
Non-diffusable
- Globulin
- Albumin (most)
DIffusable
- Complexed
- Ionized (free)
3
Q
What form(s) of Ca is/are monitored and regulated by the body?
A
ONLY ionized Ca!
4
Q
How are ionized Ca levels affected by acid-base status?
A
Acidosis -> Ca displaced form albumin -> increased ionized Ca
(alkalosis decreases iCa)
5
Q
Serum Ca levels must be corrected for what?
A
Plasma protein changes
- Hydration
- Excess production/loss of protein (liver or kidney disease)
Corrected serum Ca for albumin: Serum Ca* + 0.8 (4 - albumin**)
*Serum Ca in mg/dL
**Albumin in g/dL
6
Q
Correct the serum Ca for albumin of 2.5 and Serum Ca of 8.2
A
Corrected Ca = Serum Ca + 0.8 (4 - albumin)
Corrected Ca = 8.2 + 0.8 (4-2.5)
Corrected Ca = 9.4
7
Q
What are the effects of PTH?
A
Increase serum Ca
- Increase bone resorption
- Increases renal production of calcitriol
- Increase renal Ca reabsorption
Decrease serum PO4
- Increases PO4 excretion
8
Q
What are the effects of calcitonin?
- Secreted by what cells/organ
A
Lower serum Ca (not very significant role)
- Produced by parafollicular cells (C-cells) of thyroid
9
Q
Describe the parathyroid glands
- Number
- Location
A
Usually 4/person
- 5% have more, 5% have fewer
Found posterior to thyroid or in upper mediastinum
10
Q
Describe the Ca sensing receptor?
- Expressed by what cells
- Mechanism (in parathyroid)
A
CaSR
- Expressed by: parathyroid, kidney, bone marrow, osteoclasts, breast, C-cells, stomach gatrin cells
Mechanism:
- GPCR (7 TM segments)
- Ca binds receptor when levels are high
- Stimulates PLC-beta -> IP3 -> high cytosolic Ca
- Blocks secretion of PTH from parathyroid
11
Q
What stimulates PTH secretion?
A
- Low Calcium
- High Phosphate
12
Q
Describe Vitamin D synthesis
A
- D3 generated in the skin (UV-B rays)
- Diet (cholecalciferol/ergocolciferol)
- Animals: fish oils, eggs, fortified milk/cereal
- Plants (Vit D2- ergo)
- D3 and D2 need to be metabolized into active hormones; this is regulated by PTH (1a-OHase activity)
- Active Vit D works on intestine and bone
13
Q
What are effects of active Vitamin D?
A
Increase Ca AND PO4 in ECF
- Increase gut uptake of Ca and phosphate
- Bone:
- Increase osteoblast activity to increase matrix protein synthesis
- Increase osteoclast activity (via OB release of OAFs) to increase Ca release
- Increase renal reabsorption of Ca and phosphate
14
Q
What can cause hypercalcemia?
A
- Primary hyperparathyroidism (#1)
- Malignancy (#2)
- Small cell carcinoma (mostly squamous!)
- Renal cell carcinoma
- Breast
- Multiple myeloma
- Mets
- Familial Hypercalcemic Hypocalcuria (AD)
Also:
- Excess Vitamin A/D
- Milk of magnesia (tums)
- Immobilization
- Infection (TB, coccidio, histo)
- Sarcoid
- Drugs
- Renal failure (3’ hyperparathyroidism)
- Thyrotoxicosis
- Addison’s
- Padget’s of bone (in conjunction w/ immobilization)
15
Q
What drugs may cause hyeprcalcemia?
A
- Thiazides
- Theophylline
- Lithium
16
Q
What are the most common causes of primary hyperparathryoidism?
A
-
Adenoma (90%)
- Autonomous secretion of PTH by parathyroid adenoma -
Hyperplasia (7%)
- Typically occurs in hereditary syndromes (MEN1 and MEN2a have component of this) - Carcinoma (3%)
17
Q
What will you see in labs with primary hyperparathryoidism?
A
- High PTH
- High Ca
- Low phosphorus
18
Q
What are the clinical manifestations of 1’ hyperparathryoidism?
A
- Height loss
- Osteitis fibrosa cystica
19
Q
What is Osteitis Fiborosa Cystica
- Associated with what conditions
- Histologically
- Grossly
- Radiologically
- Clinically
- Treatment
A
- Associated with severe 1/2’ hyperparathyroidism
- Increased numbers of osteoclasts and fibroblasts
- Accumulation of “hemosiderin” in tumor gives them the name “brown tumors”
Radiologic findings:
- Subperiosteal resorption
- Bone cysts
Clinical:
- Severe hypercalcemia
- Bone pain
Treatment:
- Surgical resection of parathyroid tumor
- Causes rapid reversal of clinical findings!
20
Q
What is seen here?
A
Resorption of distal phalanx (symptom of 1’ hyperparathyroidism?)
21
Q
What is seen here?
A
Bone cysts in primary hyperparathyroidism
22
Q
What is secondary hyperparathyroidism
- Causes
- Labs
A
Causes:
- Renal insufficiency:
- Hyperphosphatemia
- Hypocalcemia (due to decreased 1,25(OH)Vita D production)
- Intestinal malabsorption
- Hypocalcemia (from Vit D deficiency)
Labs:
- High PTH
- Low Ca
- High (renal) or low (malabsorption) phosphorus
23
Q
What are consequences of 2’ HPT?
A
Osteitis fibrosa cystica
- Cysts/nodules
- Sub-periosteal resorption of bone
24
Q
What is teritary hyperparathyroidism?
- Causes
- Labs
- Treatment
A
Causes
- Autonomous PTH secretion
- PTH gland hyperplasia
Labs:
- High Ca
- Variable phosphorus
- High PTH
Treatment:
- Parathyroidectomy
- Calcimimetic (bind CaSR and suppress PTH)
25
How is malignancy related to hypercalcemia (mechanisms, 4)?
- **PTH related protein (PTHrP)** that mimics PTH (amino terminus binds normal PTH receptor)
- **Osteoclast** **activating** factors (i.e. cytokines)
- **Osteolytic bone** **lesions** (myeloma, breast carcinoma)
- **Ectopic production of calcitriol** (lymphoma)
26
What tumors produce PTHrP
- Mechanism of action
- Lab values
**Solid tumors:**
- Squamous cell carcinomas (lung, esoph, H/N, skin, cervix)
- Renal, bladder
- Breast
- Ovarian
**Lymphoma** due to HTLV-1
Action: mimics PTH
_Labs:_
- Low PTH
- High C
- Low PO4
27
What is the effect of an inactivating mutation of the CaSR?
In what condition(s) is this seen?
(Calcium sensing receptor)
- Inactivating mutation -\> failure of activation by calcium
- Ca levels falsely perceived as low
- PTH is still released (hyperparathyroidism)
This occurs in **Familial Hypocalciuric Hypercalcemia**
28
Describe Familial Hypocalciuric Hypercalcemia
- Distinct from 1' hyperparathryoidism
- Genetics
- Mechanism
- Symptoms
- Diagnosis
- Treatment
- 1' hyperparathryoidism typically has normal/high urine Ca, while it is low in FHH (FEca under 1%)
- **Autosomal dominant**; heterozygous mutation (overall disease manifestation is less severe)
- Increased "set point" for Ca-regulated PTH secretion (PTH released even when Ca not that low; CaSR is inactivated and PTH continues to be secreted even when Ca is high)
- _Symptoms_: mild, asymptomatic, found incidentally on labs (PTH normal/high but serum Ca is not low)
- FHx of hypercalcemia
- No treatment needed
29
What are signs/symptoms of hyperalcemia?
Bones, stones, moans, and groans
- **Bones**: osteoporosis, fractures, osteitis fibrosa cystica, brown tumor of jaw, bone pain/arthralgias
- **Stones**: nephrolithiasis, renal failure
- **Moans** (**abdominal**): nausea, constipation, peptic ulcer disease, acute pancreatitis
- **Groans** (**psychiatric**): altered mental status, lethargy, coma, psychosis, decreased concentration, depression
_ALSO:_
- Band keratopathy (corneal calcification)
- HTN, cardiac arrhythmia, shortened QT interval
30
What is acute management of hypercalcemia?
**1. Hydrate aggressively with IV saline**
**2. Loop diuretic** (furosemide) after\* adequate hydration
**3. Decrease bone resorption**
- Bisphosphonates IV (pamidronate/zoledronate once)
* Later onset (2-3d), but longer sustained duration of action
- Calcitonin (4 to 8 IU/kg sc q12h)
* Earlier onset (1/2-1d), but short duration of action (2-3d)
**4. Glucocorticoids when indicated**
- Vit D intoxication, granulomatous diseases or hematologic malignancies mediated by Vit D
**5. Gallium nitrate or plicamycin**
- For refractory hyperCa
- Beware of toxicities (renal, bone marrow, hepatic)
**6. Dialysis** (against low Ca bath)
31
Is QT long or short in hypercalcemia?
Short QT (Long QT in hypocalcemia)
32
What are indications for surgery in 1' hyperparathryoidism?
_Symptomatic:_
- Nephrocalcinosis, nephrolithiasis, osteitis fibrosa cystica
- Altered mental status
_Asymptomatic:_
- Corrected serum Ca \> 1 mg/dL above normal
- Renal: Decreased Creatinine Clearance (CrCl under 60%)
- 24 hr urinary calcium \> 400 mg, increased stone risk or presence of nephrolithiasis or nephrocalcinosis by radiograph, ultrasound, or CT
- Skeletal: T-score
33
What are major/minor causes of hypocalcemia?
_Major:_
- Vitamin D deficiency
- Exhaustion of skeletal Ca stores with repeated pregnancies
- Hypoparathryoidism (surgical, idiopathic)
_Minor:_
- Pseudo-hypoparathyroidism-PTH resistance
- “Hungry bones” following surgery for primary hyperparathyroidism
- Activating mutation of CaSR\*\*
- Mg++ deficiency (severe)
- Pancreatitis (chelation effect)
34
Rickets and osteomalacia may result from what?
Hypocalcemia
35
What is rickets? Osteomalacia?
- Effects/observations
- Causes
Rickets occurs in kids and osteomalacia in adults
- Impaired mineralization of new bone matrix (osteoid)
- Surfaces of cortex and trabeculae have thickened layer of unmineralized osteoid
- Disorganized bone susceptible to deformity/fracture
_Causes:_
- Inadequate exposure to sunlight
- Culture
- Latitude
- Sunscreen (SPF 8)
- Decreased dietary intake
- Liver/kidney disease
- Malabsorption
- Genetic defects in Vit D receptor (resistance)
36
What is seen in nutritional rickets (example)?
- Cupping and fraying of distal metaphysis of radius and ulna
- Gen varum (bowing of legs)
37
What is seen here?
**Rachitic rosary**
- Seen in hypocalcemia
38
Difference between Vitamin D:
- Deficiency
- Insufficiency
- Deficiency (under 20)
- Insufficiency (under 30)
39
What are clinical features of Osteomalacia?
- Low serum calcium or phosphorus, or both
* Key point: Low calcium X phosphorus product
- Elevated level of serum alkaline phosphatase
- Bone pain
- Proximal muscle weakness
- Deformity
- Pseudofractures (“Looser’s Zone” or Milkman’s fractures):
* Indicative of severe osteomalacia
* Weak site predisposed to traumatic fracture
40
What is seen here?
Looser's zone (pseudofractures)
- Seen in osteomalacia
41
What are signs and symptoms of hypocalcemia?
_Symptoms_ (Ca under 7 mg/dL)
- Perioral, tongue and extremity paresthesias
- Facial spasms
- Myalgias
- Muscle cramps (back, legs)
_Signs:_
- Tetany
- Carpopedal spasm
- Chvostek's sign
- Trousseau's sign
- Arrhythmia
- Prolonged QT interval
42
What is Chvostek's sign?
Neuromuscular irritability seen in hypocalcemia
- Tap the facial nerve in front of the ear (below the zygomatic arch)
- Positive sign is contraction of the ipsilateral facial muscles
43
What is Trousseau's sign?
Seen in **hypocalcemia**
- Inflate BP cuff above systolic (10 mmHg) and hold; results in:
- Carpal spasm
- Muscular contraction at wrist and MCP joints
- Hyperextension at fingers
- Flexion of thumb
44
How to treat acute/severe hypocalcemia?
**1. Calcium - PO ("elemental")**
- IV infusion
**2. Normalize Mg**
- Will allow for normal PTH secretion
**3. 1,25(OH)Vit-D3**
- Especially useful if hypoparathryoid
- Calcitriol
**4. Thiazide diuretic**
- Increases renal reabsorption of Ca
- Include amiloride to avoid hypokalemia
