Endo: Clinical Disorders Of Calcium And Phosphorus

Front 1

Role of Calcium and phosphorus in body

Back 1

Calcium:
Extracellularly: nerve, muscle function, clotting
Intracellularly: secondary messenger
Large gradient

Phosphorus:
Major intracellular ion used in ATP production, membrane phospholipids, and bone matrix, well absorbed in GI, concentrated by renal excretion

Front 2

Major determinants of Calcium and Phosphorus homeostasis

Back 2

Diet (Ca++ and Vit D), Parathyroid hormone, FIbroblast growth factor 23 (FGF-23)

Front 3

Parathyroid role, use of Ca++ and Mg++

Back 3

Glands emerge from brachial pouches and descend to neck to posterior thyroid

Req. magnesium to function properly (def can lead to hypocalcemia)

Sense blood calcium and respond to changes by releaseing PTH

ALWAYS consider magnesium deficiency in pt with hypocalcemia, hyperphosphatemia and low PTH due to defunctional parathyroid gland

Front 4

Alcoholism hypocalcemia pathophys

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Profound magnesium deficiency leading to compromised parathyroid gland function

Front 5

PTHrP

Back 5

PTH related peptide, a substance which some tumors secrete leading to hypercalcemia by activating PTH receptors

Front 6

PTH targets

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Bone - activates osteoblasts which causes causes an augmentation of alkaline phosphatase, these osteoblasts communicate with osteoclasts resulting in a NET Ca++ and Phosphorus releasen to blood

Kidney - PTH induces conversion of 25-OH Vit D to active 1,25-OH Vit D which acts on gut to increase calcium and phosphate absorption

Also PTH induces kidney to increase calcium resorption and decrease phosphate resorption = phosphaturia

Net is to selectively increase Calcium without so much phosphate

PTH = phosphate trashing hormone

Front 7

Circulating forms of Ca

Back 7

Binding proteins include albumin (80%) and calcium binding protein (20%) and a little bound with an anion like bicarb, lactate, citrate. changes in either affect total serum calcium

Ionized or "free" calcium is functional form both intracellularly and extracellulary

Split is 50/50 bound and free

Shifts a lot between bone, kidney, blood so total calcium levels change greatly

Front 8

Conditions which influence total serum calcium

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a) Changes in binding proteins - CANNOT interpret total Ca++ without knowing plasma albumin levels seen in PREGNANCY and MYELOMA

b) Changes in pH alter FREE calcium BUT NOT TOTAL
Acidosis = increased ionized calcium
Alkalosis = decreased ionized calcium - binds albumin more and can lead to tetany
pH 0.1 unit changes Ca++ o.2mg/dL the other way

c) Other things like anions (lactate, bicarb, citrate), drugs, FFAs which interfere with protein binding

Front 9

Calculating corrected Ca++ in decreased albumin pt

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For every 1g/dL reduction in albumin below 4g/dl add 0.8 mg/dl Ca to measured calcium level

Ex. 3.6 g/dL albumin = 0.4 x 0.8 + measured calcium to correct

Doesn't hold if pt has significant acid-base disorders, best to assess homeostasis by directly measuring ionized calcium levels

Front 10

Normal negative feedback for Calcium

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When plasma calcium low, PTH high
when plasma calcium high, PTH low

PTH changes mediated by CaSR (very sensitive to changes)

Front 11

PTH and Calcium levels seen in
a) Primary Hyperparathyroidism
b) Secondary Hyperparathyroidism
c) Hypoparathyroidism
d) PTH independent hypercalcemia

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a) HIGH serum calcium, HIGH PTH - hyperplasia, adenoma, carcinoma of the parathyroids
b) LOW serum calcium, HIGH PTH - ex. chronic renal failure and hypercalciuria
c) LOW serum calcium, LOW PTH - ex surgical removal, autoimmune destruction
d) HIGH serum calcium, LOW PTH - ex, excess calcium ingestion, cancer (PTHrP)

PTH normal is 10-65 pg/mL to maintain Ca between 8.5-10.5 mg/dL

Front 12

Vitamin D sources, activation, role

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Sources: sun exposure (harder to get if darker skin), fish, dairy

Activation: Hydroxylated in liver by 25 hydroxylase to 25-OH Vit D. That converted to 1,25(OH)2 Vit D by 1 alpha hydroxylase in kidney (also in normal and pathologic tissues eg. macropages and lymphocytes).

Kidney 1,25(OH)2 Vit D increases PTH secretion, bone resoprtion, gut calcium resoption

Non-calcitropic/extrarenal - helps in immunity in macrophages and lymphocytes, causes breast, colon and prostate to proliferate, kidney renin secretion, insulin secretion and others

More autocrine functions

Front 13

Fibroblast Growth Factor-23 Source, Role

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AKA "Phosphatonin" phosphaturic factor

Made by osteoblasts, modulates urinary phosphate excretion to inhibit PCT phosphate absorption (increases wasting)

Leads to hypophosphatemia in XLH, ADHR, MAS, TIO

Impairs 1,25(OH)2 Vit D synthesis and bone mineralization

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Most common cause of hypercalcemia in ambulatory setting

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Primary hyperparathyroidism

High Ca++ and High PTH

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Causes of Hypercalcemia with High PTH

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a) Primary Hyperparathyroidism - mostly solitary adenoma, but could be familial for 4 gland hyperplasia

b) Familial hypocalciuric hypercalcemia (FHH) - MILD elevation due to inability to excrete calcium in urine (24 hr urine calcium excretion lower than expected), normal or high magnesium, need family history or history of "failed surgeries

c) Hydrochlorothiazide - mild reclamation of calcium in renal tubules when start drug

d) Lithium - resets parathyroid gland feedback so increased in blood, do not restrict dietary sources

e) Parathyroid cancer - rarely found but levels become INCREDIBLY high while pt mostly asymptomatic

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Causes of hypercalcemia with Low PTH

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a) Unrelenting or untreated hyperthyroidism or thyrotoxicosis - mild elevations b/c thyroid hormone activates osteoblasts and causes increased bone turnover

b) Cortisol deficiency (adrenal insufficiency) - midly elevate because cortisol attenuates absorption of calcium from gut

c) Multiple myeloma due to osteoclast activating factor

d) Malignancy releasing PTHrP (pretty common)

e) Vit D mediated granulomatous disease - SARCOIDOSOS

f) Leukemia, lymphomas through Vit D process

g) Vit D toxicity with low 1,25(OH)2D

h) Vit A Toxicity

Front 17

Calcitriol

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Product seen in granulomatous disease (sarcoid, TB, fungal, leprosy, etc), Hodkin's disease that increases calcium levels but will have low PTH

Front 18

Immobilization effect on Ca

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HYPERCALCEMIA due to rhambdomyolysis in immobilization

Due to PTH release to waste the excess phosphorus released. This absorbs more calcium as a byproduct.

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Diagnostic Approach to Hypercalcemia

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Confirm that the hypercalcemia is real

1. Measure PTH
Identifies PHPT, FHH, HCTZ, Lithium, Parathyroid Ca (IF HIGH)

2. Measure PTHrP (IF PRESENT)
Identifies some malignancies

3. Measure 1,25(OH)2D (IF HIGH)
Identifies malignancy, granulomatous ds

4. Measure 25-OHD (IF HIGH)
Identifies vitamin D toxicity

5. Measure TFTs, cortisol
Identifies Hyperthyroidism, Addison’s disease
(shouldn’t be a surprise)

6. CBC, SPEP, urine protein electrophoresis
Identifies myeloma

Front 20

Causes of Hypocalcemia

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1) Increased PTH
a) Vit D deficiency - most common
b) Genetic abnormalities causing Vit D resistance
c) Hyperphosphatemia secondary to chronic kidney disease, tumor lysis syndrome, rhabdomyolysis, or administration of large boluses of phosphorus (Fleet's enema)

2) Decreased PTH
a) Surgical hypoparathyroidism
b) Autoimmune hypoparathyroidism (any age, get labs in context of norm magnesium milieu
c) Magnesium deficiency

Front 21

Causes of Vit D deficiency

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Dietary def
GI disorders
Bariatric surgery
Accelerated Vit D metabolism from meds (eg. Dilantin)

Front 22

Most common cause of hypocalcemia

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MAGNESIUM deficiency

Due to alcoholism, diarrheal illness, renal tubular wasting

Front 23

Tumor induced hypophosphatemia/osteomalacia presentation

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HIGH HIGH FGF-23

Normal calcium, Low 1,25 (OH)2 Vit D (FGF inhibits conversion of 25D to 1,25D)

PROFOUND hypophosphatemia

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Osteomalacia/Rickets Pathology, Cause, Labs,

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Pathology: Decreased bone density (bone mass), NORM osteoid and it is due to mineralization defect

Causes:
a) Vit D deficiency/resistance - 2ndary hyperparathyroidism
b) Phosphorus deficiency

Labs: Reduced plasma Ca++ and Phosphate, Increased alkaline phosphatase (due to osteoblast activity)