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Flashcards in Calcium pathophysiology Deck (61):
1

Calcium Metabolism

a. Maintain Serum Calcium Within Narrow Range
i. Normal range is 8.5 - 10.5 mg dl
ii. 9.0 - 10.0 is the optimal range

a. Calcium lowering
mechanisms initiated
i. once Ca gets too high in the blood (over 10) will release Calcitonin

b. Calcium raising
mechanisms initiated
i. Once Ca gets to low (below 9) will release PTH


2

Calcium Metabolism
Calcium Regulating Hormones

1. Parathyroid Hormone

2. 1, 25 (OH)2 Vitamin D

3. Calcitonin

3

Calcium Metabolism
Calcium Regulating Organs

1. Bone

2. Kidney

3. Intestine

4

Parathyroid Hormone

84 Amino Acid Peptide

1. Increased Serum Calcium:
i. Increases Bone Resorption

2. Decreased Calcium Excretion at Kidney
i. Increased Phosphate Excretion

3. Increases Calcium Absorption at GI
i. Inc. 1,25 (OH)2 D
Production

5

Calcium Metabolism
PTH Effects

1. Increased Serum Calcium:
i. Increases Bone Resorption

2. Decreased Calcium Excretion at Kidney
i. Increase Phosphate Excretion

3. Increases Calcium Absorption at GI
i. Increased 1,25 (OH)2 D Production


6

Vitamin D Metabolism

a. How Vitamin D is created:
Skin: D3 Cholecalciferol

Diet: D2 Ergocalciferol
D3 Cholecalciferol

b. 25 OH Vitamin D- Major Storage Form
of Vitamin D
i. hydroxylated from Liver to make storage form
ii. is very fat soluble (thus able to store it)

c. 1,25 (OH)2 Vitamin D- Active Form of
Vitamin D
i. active form gets created from 2nd hydroxylation from Kidney

7

Calcium Metabolism
1,25 (OH)2 Vitamin D Effects

a. Will raise serum calcium and raise serum phosphate

b. Vitamin D will increase serum absorption at the GI of both phosphate and Calcium

c. Vitamin D will also increase bone resorption

8

Calcitonin

a. 32 Amino Acid Peptide

b. Parafollicular
i. C-Cells

c. decrease Serum Calcium

9

Calcium Metabolism
Calcitonin Effects

a. decreased Bone Resorption

b. decrease Serum Calcium

10

Calcium Sensor Receptor

a. Parathyroid Cell - PTH Secretion
i. low calcium will allow PTH secretion

b. Parafollicular C-Cell - Calcitonin Secretion
i. High serum Ca will lead to Calcitonin secretion

c. Renal Tubular Cell - Calcium Excretion
i. will change their level of excretion

11

Hypercalcemic Disorders

Always measure the PTH to see if elevated

1. 1o Hyperparathyroidism
i. most common type of high PTH
ii. lead to hypercalcemia
iii. *will see elevated PTH levels

2. Hypercalcemia of Malignancy
i. 2nd most major cause of hypercalcemia

3. These others account for 10%:
-Granulomatous Disease
-Vitamin D Intoxication
-Vitamin A Intoxication
-Hyperthyroidism

-Thiazide Diuretics
-Milk-Alkali Syndrome
-Immobilization
-Adrenal Insufficiency
-Acute Renal Failure

4. Familial Hypocalciuric Hypercalcemia
i. *will see elevated PTH levels

12

Case History
An 18 year old male presents for an 18 month history of right side facial swelling and a left hard palate mass.
PE: large firm right facial mass
large firm left hard palate mass
Lab: Calcium 17.0 mg/dl Phos 2.0 mg/dl
Creatinine 0.5 mg/dl Albumin 3.9 g/dl


Lab: Calcium 17.0 mg/dl Phosphorus 2.0 mg/dl
Creatinine 0.5 mg/dl Albumin 3.9 g/dl

Repeat Labs:
Calcium 17.2 mg/dl (nl: 8.5-10.3)
PTH 108 pg/ml (nl: 10-65)


Biopsy of Right Maxillary Mass:
Brown Tumor of Hyperparathyroidism


Parathyroid Surgery:
2.0 x 1.5 cm Left Inferior Adenoma

13

Primary Hyperparathyroidism
Classification

a. Adenoma 85%

b. Hyperplasia 15%
i. more enlarge tissue

c. Carcinoma < 1%

14

Primary Hyperparathyroidism
Clinical Features

a. General Sx:
Asymptomatic (> 50%)
Skeletal Disease
Kidney Disease
Gastrointestinal Disease
Psychiatric Disease

b. Specific Sx:
Arthritis
Muscle Weakness
Band Keratopathy
Hypertension
Anemia

c. *Good trick:
Bones
Stones -kidney stones
Groans
Moans

15

Hyperparathyroidism
Brown Tumor

Brown Tumor (Osteoclastoma)

a. Type of benign adenoma

b. Can occur in any bone

16

Hyperparathyroidism
Band Keratopathy

Band keratopathy is a corneal disease derived from the appearance of calcium on the central cornea. This is an example of metastatic calcification, which by definition, occurs in the presence of hypercalcemia

17

Primary Hyperparathyroidism
Diagnosis

1. Increased Serum Calcium

2. Decreased Serum Phosphate

3. Increased Serum PTH

18

Primary Hyperparathyroidism
Associations

1. Sporadic 90%
i. will see an adenoma

2. Familial 10%
i. will see hyperplasia
ii. Genes in familial
Familial HPT
MEN I
MEN IIA

19

Multiple Endocrine Neoplasia I

MEN 1 mutations have:
1. Pituitary Tumors
2. Pancreatic Islet Tumors
3. Parathyroid Hyperplasia

Germline Mutation: Menin Gene

20

Multiple Endocrine Neoplasia IIA

MEN 2A mutation have:
1. Medullary Thyroid Carcinoma
2. Pheochromocytoma
3. Parathyroid Hyperplasia

Germline mutation: Ret Gene (GDNF receptor)

21

Primary HyperparathyroidismTreatment

a. Surgery
i. Adenoma - 1 Gland
ii. Hyperplasia - 3 1/2 Glands

b. Calcimimetic Drug (Cinacalcet)
i. will lower PTH levels
ii. treat but not cure

c. Anti-Resorptive Bone Drug
i. Bisphosphonate, Denosumab
ii. use to prevent osteoperosis

22

Secondary Hyperparathyroidism

a. Parathyroid gland produce too much PTH because of another stimulus

b. Causes of Increased PTH in secondary
hyperparathyroidism:
1. Decreased Calcium
2. Increased Phosphorus
3. Decreased 1,25 Vitamin D

c. Correcting the calcium, phosphorus, or Vit D will fix the secondary hyperparathyroidism

23

Case History

A 19 year old man complains of a 2-3 week history of weakness, nausea and vomiting.
PE: BP 90/65 P 108 Dehydration

Lab: Ca 19.1 Phos 3.9 CBC normal
PTH < 1 pg/ml (nl: 10-65)

Hmmmmm Hypercalcemia with Hypothyroidism

Has possible Malignancy

24

Hypercalcemia of Malignancy

Tumor Types

Three to know generally:
1. Lung Cancer (Squamous Cell, especially)
2. Breast Cancer
3. Head and Neck Cancer

25

Hypercalcemia of Malignancy
Mediators

a. PTH Related Peptide (PTH-RP)
i. most common mediator of secondary hyperthyroidism
ii. seen in 90% of cases



b. Other ones (less than 10 %)
Transforming Growth Factors (TGFb)
Tumor Necrosis Factor (TNF)
Interleukin 1, Interleukin 6
RANK-L
DKK-1
1,25 (OH)2 Vitamin D

26

PTH Related Peptide (PTH-RP)

a. Parathyroid hormone-related protein (or PTHrP) is a protein member of the parathyroid hormone family.
i. It is occasionally secreted by cancer cells (breast cancer, certain types of lung cancer including squamous cell lung carcinoma). However, it also has normal functions.

b. PTHrP is related in function to the "normal" parathyroid hormone. When a tumor secretes PTHrP, this can lead to hypercalcemia.
i. As this is sometimes the first sign of the malignancy, hypercalcemia caused by PTHrP is considered a paraneoplastic phenomenon.

c. PTHrP shares the same N-terminal end as parathyroid hormone and therefore it can bind to the same receptor, the Type I PTH receptor (PTHR1).
i. PTHrP can simulate most of the actions of PTH including increases in bone resorption and distal tubular calcium reabsorption, and inhibition of proximal tubular phosphate transport.

27

Hypercalcemia of Malignancy
Diagnosis

1. Increased Serum Calcium

2. Decreased Serum PTH
i. the PTH-RP will suppress normal production of PTH

3. Increased Serum PTH-RP
(or other mediator)


a. PTHrP is related in function to the "normal" parathyroid hormone. When a tumor secretes PTHrP, this can lead to hypercalcemia.
i. As this is sometimes the first sign of the malignancy, hypercalcemia caused by PTHrP is considered a paraneoplastic phenomenon.

b. PTHrP shares the same N-terminal end as parathyroid hormone and therefore it can bind to the same receptor, the Type I PTH receptor (PTHR1).

28

Calcium Sensor Receptor in FHH

(Familial Hypocalciuric Hypercalcemia)

a. Parathyroid Cell - Increased PTH Secretion
i. mutation in calcium sensing receptor, won't bind to calcium properly
ii. will have new high equilibrium to calcium

b. Renal Tubular Cell - Decreased Calcium Excretion
i. mutation in calcium receptor, won't secrete calcium as well

29

Familial Hypocalciuric Hypercalcemia
Diagnosis

1. Increased Serum Calcium (mild)

2. Increased Serum PTH (mild)

3. Decreased Urinary Calcium
i. decreased Urine Calcium / Creatinine Clearance Ratio

30

Hypocalcemia Causes

1. Vitamin D Deficiency

2. Hypoparathyroidism*
i. Will measure low PTH, unlike the other disorders

3. Pseudohypoparathyroidism

4. Hypomagnesemia

5. Renal Failure

6. Liver Failure

7. Acute Pancreatitis

8. Hypoproteinemia**
** Corrected Serum Total Calcium
Add 0.8 mg/dl to total Calcium for
every 1 g/L Albumin is < 4.0 g/

31

Hypocalcemia
Clinical Features

a. Paresthesias

b. Muscle Cramps

c. Muscle Weakness

d. Chvostek’s Sign

e. Trousseau’s Sign

32

Vitamin D Disorders

a. Acquired Vitamin D Deficiency
i. Poor Oral Intake / Malabsorption
ii. Inadequate Sunlight

b. Acquired 1,25 (OH)2 Vitamin D Deficiency
i. Renal Disease
ii. Hypoparathyroidism

c. Congenital 1 Alpha Hydroxylase Deficiency
i. “Vitamin D Dependent Rickets Type 1”

d. Congenital Vitamin D Receptor Deficiency
i. “Vitamin D Dependent Rickets Type 2”

33

Nutritional Vitamin D Deficiency
Laboratory

1. decreased Serum Calcium

2. decreased Serum Phosphate

3. decreased Serum 25 (OH) Vitamin D

4. increased Serum PTH (20 HPTH)

5. increased Serum Alkaline Phosphatase
(suggests Osteomalacia)

34

Osteomalacia – Pseudofracture

Milkman’s Fracture or Looser’s Line

Osteomalacia is the softening of the bones caused by impaired bone metabolism primarily due to inadequate levels of available phosphate, calcium, and vitamin D, or because of resorption of calcium. The impairment of bone metabolism causes inadequate bone remineralization. Osteomalacia in children is known as rickets, and because of this, use of the term "osteomalacia" is often restricted to the milder, adult form of the disease. Signs and symptoms can include diffuse body pains, muscle weakness, and fragility of the bones.

a. Osteomalacia is a generalized bone condition in which there is inadequate mineralization of the bone.
i. Many of the effects of the disease overlap with the more common osteoporosis, but the two diseases are significantly different.

b. There are two main causes of osteomalacia:
(1) insufficient calcium absorption from the intestine because of lack of dietary calcium or a deficiency of, or resistance to, the action of vitamin D; and
(2) phosphate deficiency caused by increased renal losses.

c. Diffuse joint and bone pain (especially of spine, pelvis, and legs)
Muscle weakness
Difficulty walking, often with waddling gait
Hypocalcemia (positive Chvostek sign)
Compressed vertebrae and diminished stature
Pelvic flattening
Weak, soft bones
Easy fracturing
Bending of bones

35

Nutritional Vitamin D Deficiency

Repletion and Maintenance

Repletion
1. 25 OH Vitamin D < 10 ng/ml: 50,000 U Vitamin D2 BIW x 3 mos

2. 25 OH Vitamin D 10-20 ng/ml: 50,000 U Vitamin D2 QW x 3 mos

3. 25 OH Vitamin D 20-30 ng/ml: 2000 U Vitamin D3 QD

Maintenance
1. Optimal Intake: 800-1200 U/day

2. Safe Intake: 2000 U/day

3. Goal 25 Vitamin D Level: 30-100 ng/ml

36

Hypoparathyroidism
Laboratory Features

1. decreased Serum Calcium

2. increased Serum Phosphate

3. decreased Serum PTH

37

A 19 year old woman complains of episodes of numbness/tingling in her hands and feet and frequent muscle cramps.

PMH: mucocutaneous candidiasis

PE: BP 115/70 P 72 Ht 5’8’’ Wt 135 lb.
Hand developed spasm during BP check

Lab: Ca 6.8 Phos 5.4 Na 142 K 4.5
Serum PTH: 2 pg/ml (nl, 10-65)

1. decreased Serum Calcium

2. increased Serum Phosphate

3. decreased Serum PTH

38

A 23 year old woman complains of chronic numbness/tingling in her hands and feet and frequent muscle cramps.
PMH: negative Meds: none
PE: BP 125/75 P 72 Ht 5’0’’ Wt 128 lb.
Negative Chvostek’s and Trousseau’s signs
Lab: Ca 6.3 Phos 5.9 Na 144 K 4.2
Serum PTH: 188 pg/ml (nl, 10-65)

Pseudohypoparathyroidism

Laboratory Features
1.decreased Serum Calcium

2. Increased Serum Phosphate

3. Increased Serum PTH

4. Short 4th + 5th Metacarpals


39

Pseudohypoparathyroidism
Laboratory Features

1.decreased Serum Calcium

2. Increased Serum Phosphate

3. Increased Serum PTH

4. Short 4th + 5th Metacarpals

40

Pseudohypoparathyroidism

a. Pseudohypoparathyroidism is a condition associated primarily with resistance to the parathyroid hormone.

b. Those with the condition have a low serum calcium and high phosphate, but the parathyroid hormone level (PTH) is actually appropriately high (due to the low level of calcium in the blood).
i. Its pathogenesis has been linked to dysfunctional G Proteins (in particular, Gs alpha subunit).

c. The condition is extremely rare, with an estimated overall prevalence of 7.2/1,000,000 or approximately 1/140000.

41

Calcium Metabolism: Introduction

a. Calcium metabolism is the homeostatic process by which the body maintains a precisely regulated serum and extracellular fluid ionized calcium concentration.

b. The normal human body contains about 2 kg of calcium; 99% is located in the bones and teeth, 1% is in the intracellular compartment, and < 1% is in the extracellular fluid (~50% is protein-bound and ~50% is ionized).

c. A normal gradient between extracellular ionized calcium and intracellular ionized calcium is necessary for the normal function of most of the cells in the body.
i. For this reason, the serum calcium concentration is maintained within a very narrow range.

d. If the serum calcium concentration drifts outside the optimal range, multiple mechanisms are initiated to promptly return the serum calcium into the optimal range.

42

Calcium homeostasis is regulated largely by 3 hormones acting on 3 organ systems

The 3 hormones are Parathyroid Hormone (PTH), 1,25 dihydroxyvitamin D (1,25 (OH)2 Vitamin D), and Calcitonin; the 3 organ systems are the skeleton, the kidneys and the intestines.

1. PTH is an 84 amino acid peptide produced by the parathyroid glands.
i. It raises serum calcium levels by direct actions on the skeleton and kidneys and indirect actions on the intestines.
ii. PTH directly stimulates osteoclastic bone resorption, which releases ionized calcium and phosphate from the skeleton into the extracellular fluid.
iii. PTH directly inhibits renal calcium excretion but promotes renal phosphate excretion.
iv. And PTH stimulates conversion of 25 OH Vitamin D into 1,25 (OH)2 Vitamin by renal 1 alpha hydroxylase and thereby indirectly stimulates intestinal calcium and phosphorus absorption.

2. 1,25 (OH)2 Vitamin D raises serum calcium levels by directly enhancing intestinal calcium and phosphorus absorption and by promoting osteoclastic bone resorption, an effect that occurs mainly at high 1,25 (OH)2 Vitamin D levels.

3. Calcitonin is a 32 amino acid peptide produced by the parafollicular c-cells in the thyroid gland.
i. It lowers serum calcium by inhibiting osteoclastic bone resorption.

43

Large Summary of Active Vitamin D

a. 1,25 (OH)2 Vitamin D raises serum calcium levels by directly enhancing intestinal calcium and phosphorus absorption and by promoting osteoclastic bone resorption, an effect that occurs mainly at high 1,25 (OH)2 Vitamin D levels.

b. Vitamin D has two forms: Vitamin D3 (cholecalciferol) and Vitamin D2 (ergocalciferol).
i. Vitamin D2 and D3 are converted in the liver into 25 hydroxyvitamin D (25 OH Vitamin D) by the hepatic enzyme 25 hydroxylase and 25 OH Vitamin D is converted in the kidneys into 1,25 (OH)2 Vitamin D by the renal tubular enzyme 1 alpha hydroxylase.

c. PTH is the major and necessary catalyst that stimulates the 1 alpha hydroxylase enzyme. 25 OH Vitamin D is mostly inactive but is the major storage form of Vitamin D; 1,25 (OH)2 Vitamin D is the active form that promotes intestinal calcium and phosphorus absorption.

44

Hypercalcemia
Important Summary

a. Hypercalcemia can have multiple causes but approximately 90% of cases are due to primary hyperparathyroidism or hypercalcemia of malignancy.

b. Measurement of a serum PTH level is the key test in the differential diagnosis of hypercalcemia.

c. PTH is elevated or high normal in Primary Hyperparathyroidism and the rare congenital disorder, Familial Hypocalciuric Hypercalcemia. PTH levels are low in all other causes of hypercalcemia.

d. List of Hypercalcemia disorders to know

1. Primary Hyperparathyroidism (↑ PTH)
2. Familial Hypocalciuric Hypercalcemia (↑ PTH)

Other ones: (PTH will be low)
Hypercalcemia of Malignancy
Granulomatous Disease
Vitamin D or A Intoxication
Many others....

e. Serum intact PTH levels are elevated or high normal (inappropriately normal) in patients with primary HPTH, whereas intact PTH levels are low or undetectable in almost all other common causes of hypercalcemia

45

Primary Hyperparathyroidism

*Great Summary

a. Primary Hyperparathyroidism (HPTH) is a condition in which excessive PTH production is produced by a primary disorder of one or more parathyroid glands.

b. A solitary parathyroid adenoma is the culprit in ~85% of cases, whereas parathyroid hyperplasia is the cause in ~15% of cases; < 1% of cases are due to parathyroid carcinoma.
i. This disorder is sporadic in 90% of cases, and familial in 10%.

c. Almost all familial cases of HPTH (familial HPTH, Multiple Endocrine Neoplasia 1, Multiple Endocrine Neoplasia 2A) result from hyperplasia rather than an adenoma.

46

Familial Hyperparathyroidism

A. Familial Hyperparathyroidism – Isolated

B. Familial Hyperparathyroidism Associated with Syndromes

1. Multiple Endocrine Neoplasia Type 1 (Menin Gene Mutation)
a. Pituitary Tumors
b. Pancreatic Islet Tumors
c. Parathyroid Hyperplasia

2. Multiple Endocrine Neoplasia Type 2A (Ret Gene Mutation)
a. Medullary Thyroid Carcinoma
b. Pheochromocytoma
c. Parathyroid Hyperplasia

47

MET 1 and MET2A

1. Multiple Endocrine Neoplasia Type 1 (Menin Gene Mutation)
a. Pituitary Tumors
b. Pancreatic Islet Tumors
c. Parathyroid Hyperplasia

2. Multiple Endocrine Neoplasia Type 2A (Ret Gene Mutation)
a. Medullary Thyroid Carcinoma
b. Pheochromocytoma
c. Parathyroid Hyperplasia

48

Primary Hyperparathyroidism

Clinical Summary

a. Primary HPTH occurs more commonly in women and after age 50.

b. In over 50% of affected people, this disorder is discovered by the finding of an elevated serum calcium level on routine biochemical screening in an otherwise asymptomatic individual.

c. When symptomatic, the classically described features are osteoporosis/osteopenia, kidney stones, gastrointestinal pain and psychiatric disturbances; this set of features gave rise to the description, “bones, stones, groans and moans”.

d. Other clinical features include arthritis, muscle weakness, band keratopathy, hypertension and anemia.
i. Occasionally affected patients may develop chondrocalcinosis and episodes of pseudogout.

e. The biochemical features seen on initial testing are high serum calcium and low serum phosphate, both due to the above described systemic effects of PTH.

f. Serum intact PTH levels are elevated or high normal (inappropriately normal) in patients with primary HPTH, whereas intact PTH levels are low or undetectable in almost all other common causes of hypercalcemia

49

Lab Findings for Primary Hyperparathyroidism

*Critical Summary

a. The biochemical features seen on initial testing are high serum calcium and low serum phosphate, both due to the above described systemic effects of PTH.

b. Measurement of serum intact PTH level will then clinch the diagnosis. Serum intact PTH levels are elevated or high normal (inappropriately normal) in patients with primary HPTH, whereas intact PTH levels are low or undetectable in almost all other common causes of hypercalcemia

c. When symptomatic, the classically described features are osteoporosis/osteopenia, kidney stones, gastrointestinal pain and psychiatric disturbances; this set of features gave rise to the description, “bones, stones, groans and moans”.

50

Primary Hyperparathyroidism
Treatment

a. Primary HPTH can only be cured by surgery.
i. Removal of a solitary parathyroid adenoma by minimally invasive parathyroid surgery (MIPS) is a highly successful procedure in the hands of an experienced surgeon.

b. Parathyroid hyperplasia, however, requires removal of 3 ½ parathyroid gland, with the remaining ½ gland being left in situ or auto-transplanted into a neck strap muscle or a forearm muscle.
i. Since many, if not most, patients have only mild and asymptomatic HPTH, surgery is not always necessary.

c. Many physicians suggest oral bisphosphonate therapy (alendronate, risedronate, ibandronate) for patients who are not candidates for surgery.
i. Bisphosphonates have been shown to increase bone mineral density in patients with primary HPTH but they have not yet been shown to reduce fractures in these patients. Consequently, bisphosphonates are not approved by the FDA for treatment of primary HPTH and therefore their use in this condition must be considered off label.

51

Hyperparathyroidism: Conditions Where Surgery is Recommended

(dont memorize)

1. Serum Calcium > 1 mg/dl above normal range

2. Creatinine Clearance < 60 ml/min

3. BMD T-Score < -2.5 or History of Fragility Fractures

4. History of Kidney Stones

5. Age < 50 Years

52

Secondary HPTH (Hyperparathyroidism)

a. Secondary HPTH is a condition in which excessive PTH secretion occurs as a compensatory response to another primary disorder of calcium, vitamin D or phosphorus.

b. The key to the diagnosis of secondary HPTH is the finding of an elevated serum PTH level in association with low or low normal serum calcium, low 25 OH Vitamin D, an elevated or high normal serum phosphorus, or significantly reduced estimated glomerular filtration rate (eGFR);
i. This is in distinct contrast to primary HPTH in which the serum calcium level is elevated and the serum phosphorus concentration is low or low normal.

c. Table-Secondary Hyperparathyroidism: Most Common Causes
1. Calcium Deficiency
2. Vitamin D Deficiency
3. Idiopathic Hypercalciuria
4. Chronic Kidney Disease (Stages 4 and 5)

53

Key Diagnosing between Primary and Secondary Hyperparathyroidism

a. The key to the diagnosis of secondary HPTH is the finding of an elevated serum PTH level in association with low or low normal serum calcium, low 25 OH Vitamin D, an elevated or high normal serum phosphorus, or significantly reduced estimated glomerular filtration rate (eGFR)
i. Most Common Causes
1. Calcium Deficiency
2. Vitamin D Deficiency
3. Idiopathic Hypercalciuria
4. Chronic Kidney Disease (Stages 4 and Stage 5)


b. This is in distinct contrast to primary HPTH in which the serum calcium level is elevated and the serum phosphorus concentration is low or low normal.
i. Primary Hyperparathyroidism (HPTH) is a condition in which excessive PTH production is produced by a primary disorder of one or more parathyroid glands.
ii. A solitary parathyroid adenoma is the culprit in ~85% of cases, whereas parathyroid hyperplasia is the cause in ~15% of cases

54

Hypercalcemia of Malignancy

a. Hypercalcemia of malignancy occurs when solitary, metastatic or hematologic malignancies secrete hormones, cytokines or other mediators that promote aggressive local or diffuse osteoclastic bone resorption, flooding the circulation with calcium and thereby causing hypercalcemia.

b. The most common causes of hypercalcemia of malignancy are carcinomas of the lung (especially squamous cell), breast, head and neck, kidney, bladder, pancreas and ovary, multiple myeloma and lymphomas.

c. The most commonly identified mediator is Parathyroid Hormone Related Peptide (PTH-RP), which is a 141 amino acid peptide that has complete homology with PTH in the first 13 amino acids, the segment of the molecule that binds to the PTH receptor to stimulate bone resorption.

d. The diagnosis is made by finding hypercalcemia associated with a suppressed or undetectable serum PTH level in a patient with a known or suspected malignancy.

55

Familial Hypocalciuric Hypercalcemia

*Important Summary

a. Familial Hypocalciuric Hypercalcemia (Familial Benign Hypercalcemia) is a rare autosomal dominant disorder that results from inherited inactivating mutations of the calcium sensor receptor (CaSR).

b. Impaired CaSR function results in the inability of parathyroid cells and renal tubular cells to recognize fluctuations in the serum calcium level, with resultant excessive PTH secretion and reduced urinary calcium excretion.

c. This condition is the only other hypercalcemic disorder besides primary hyperparathyroidism in which the serum intact PTH level is elevated or high normal.

d. The diagnosis is made by finding mild hypercalcemia, mildly elevated serum PTH, very low urinary calcium excretion with a calcium/creatinine clearance ratio (Uca x Pcr / Pca x Ucr) < 0.01 and a family history of this disorder in first degree relatives. The condition does not cause complications and requires no specific therapy. Importantly, parathyroid surgery should be avoided.

56

Hypocalcemia

a. Some Causes of Hypocalcemia:
Vitamin D Deficiency
Renal Failure
Hypoparathyroidism (↓ PTH)
Liver Failure


b. Symptoms of hypocalcemia include paresthesias, muscle cramps, muscle weakness, Chvostek’s sign (facial wink when tapping the facial nerve), and Trousseau’s sign (carpopedal spasm when a sphygmomanometer is maintained above systolic blood pressure for 2 minutes).

c. Measurement of 25 OH Vitamin D and a serum PTH level are the key tests in the differential diagnosis of hypocalcemia.
i. PTH is low in Hypoparathyroidism but tends to be high normal or elevated in all other causes.

d. Hypomagnesemia causes hypocalcemia because it impairs PTH secretion and causes resistance to the peripheral actions of PTH.

e. Renal disease and liver disease cause hypocalcemia primarily by interfering with Vitamin D metabolism.
i. Hypocalcemia occurs in acute pancreatitis due to precipitation of calcium salts with products of intra-abdominal lipolysis (saponification).

57

Clinical Finding of Hypocalcemia

a. Symptoms of hypocalcemia include:
i. paresthesias
ii. muscle cramps
iii. muscle weakness
iv. Chvostek’s sign (facial wink when tapping the facial nerve)
v. Trousseau’s sign (carpopedal spasm when a sphygmomanometer is maintained above systolic blood pressure for 2 minutes).

b. Measurement of 25 OH Vitamin D and a serum PTH level are the key tests in the differential diagnosis of hypocalcemia.

c. PTH is low in Hypoparathyroidism but tends to be high normal or elevated in all other causes.

58

Vitamin D Deficiency

Summary

a. The most common type of acquired Vitamin D deficiency results from inadequate intake or absorption of Vitamin D combined with insufficient sunlight exposure.

b. Since Vitamin D is essential for normal intestinal absorption of calcium and phosphorus, severe Vitamin D deficiency can cause hypocalcemia, hypophosphatemia, secondary hyperparathyroidism and eventually osteomalacia in adults and rickets in children.

c. Laboratory abnormalities in Vitamin D deficient patients include low or low normal serum calcium and phosphorus, increased alkaline phosphatase, elevated serum PTH values, low urinary calcium excretion and low serum 25 OH Vitamin D levels.

d. Radiologically, osteomalacia manifests as fractures and pseudofractures, also known as Milkman’s fractures or Looser’s lines; pseudofractures are felt to represent linear areas of bone demineralization at sites where arteries come into contact with bone surfaces.

e. Rickets is manifested by long bone bowing, flaring of the ends of long bones and delayed epiphyseal calcification.

59

Hypoparathyroidism

Good Summary

a. Hypoparathyroidism occurs most often as a result of damage to or removal of the all parathyroid glands during thyroid, parathyroid or head and neck surgery.

b. Idiopathic hypoparathyroidism is an autoimmune disorder that results in immune-mediated destruction of the parathyroid glands.
i. Idiopathic hypoparathyroidism may be a part of the Autoimmune Polyendocrine Syndrome Type 1 (APS I) where it occurs together with adrenal insufficiency (autoimmune adrenalitis), hypothyroidism (Hashimoto’s thyroiditis) and chronic mucocutaneous candidiasis.


c. Hypoparathyroidism should be suspected when hypocalcemia is found in conjunction with hyperphosphatemia.

d. The diagnosis depends upon finding a serum PTH level that is low or low normal in the presence of hypocalcemia.
i. Low serum calcium in hypoparathyroid patients results from impaired osteoclastic bone resorption, impaired conversion of 25 OH Vitamin D into 1,25 (OH)2 Vitamin D, and excessive urinary calcium excretion.

e. Treatment of this condition consists of supplementation with calcium, Calcitriol [since endogenous 1,25 (OH)2 production is impaired], and the use of a thiazide diuretic (to reduce excessive urinary calcium excretion).

60

Hypoparathyroidism Lab Findings

a. Hypoparathyroidism should be suspected when hypocalcemia is found in conjunction with hyperphosphatemia.

b. The diagnosis depends upon finding a serum PTH level that is low or low normal in the presence of hypocalcemia.

c. Low serum calcium in hypoparathyroid patients results from impaired osteoclastic bone resorption, impaired conversion of 25 OH Vitamin D into 1,25 (OH)2 Vitamin D, and excessive urinary calcium excretion.

61

Pseudohypoparathyroidism

a. Pseudohypoparathyroidism is a rare genetic disorder that results from an inherited inactivating mutation in the Gs alpha subunit or other downstream signaling element in the PTH receptor response pathway.
i. As a result of this mutation, patients are resistant to the action of PTH.

b. Clinical features include hypocalcemia, hyperphosphatemia and elevated serum PTH levels.
i. Many affected patients also have shortened metacarpals, especially the 4th and 5th metacarpals, a condition also know as Albright’s Hereditary Osteodystrophy.

c. Low serum calcium in pseudohypoparathyroid patients results from impaired osteoclastic bone resorption, impaired conversion of 25 OH Vitamin D into 1,25 (OH)2 Vitamin D, and excessive urinary calcium excretion.

d. Treatment is similar to that of hypoparathyroidism, consisting of supplementation with calcium, Calcitriol (since endogenous 1,25 (OH)2 production is impaired), and the use of a thiazide diuretic (to reduce excessive urinary calcium excretion).