Old - Jim - Bone Pathophysiology

Front 1

Pathophysiology of Hypercalcemia

I. Review of Mineral Metabolism

A. Response to hypocalcemia:
What are the two hormones that regulate serum levels of calcium, (+phosphorus)?

Back 1

Parathyroid hormone and vitamin D

Front 2

Pathophysiology of Hypercalcemia

I. Review of Mineral Metabolism
(Response to hypocalcemia:)

Serum _________ controls the synthesis and release of PTH via the __________ on the surface of ______ cells in the _________ and cells in the _______.

When serum calcium falls the CaSR is turned off, intracellular calcium is ________ which results in an increase in ___________.

Back 2

calcium

calcium sensing receptors (CaSR)

chief cells -- parathyroid
+ cells in the kidney

reduced

PTH gene transcription and PTH secretion

Front 3

Pathophysiology of Hypercalcemia

I. Review of Mineral Metabolism
(Response to hypocalcemia:)

Increased PTH (secreted by chief cells in parathyroid in response to low Ca) activates receptors located on target cells in bone and kidney, and causes several actions:

Bone?
Kidney?
Intestine?

Phosphorus?

Back 3

1) increased bone resorption via osteoclasts, releasing both calcium and phosphorus into the extracellular fluid;

2) increased resorption of calcium from glomerular filtrate, and

3) increased conversion of precursor 25-hydroxycholecalciferol (25OHD3) to the active
hormone 1,25-dihydroxycholecalcifierol (1,25OH2D3), which in turn increases absorption of calcium and phosphorus from the gastrointestinal tract.

4) decrease proximal tubular reapsorption of phosphorus (TRP) and thereby enhanced urinary phosphorus excretion prevents hyperphosphatemia.

Front 4

Pathophysiology of Hypercalcemia


I. Review of Mineral Metabolism
(Response to hypocalcemia:)


*******
The net response to hypocalcemia is to increase ECF ________ without increasing ECF _________.

Back 4

calcium

phosphorous

Front 5

Pathophysiology of Hypercalcemia

I. Review of Mineral Metabolism
(Response to hypocalcemia:)

Calcium Sensing Receptor (CaSR)
(1) Receptor type? Where is it found?
(2) Second messenger? Effect?
(3) Effect in kidney?

Back 5

1. G protein-coupled
surface of parathyroid cells and in renal tubule cells.

2. Elevation in extracellular calcium => CaSR => phospholipase C/inositol-1,4,5 triphosphate/Ca 2+ signaling pathway => reduced PTH production/secretion => return of serum calcium toward normal.

3. CaSRs throughout the nephron (primarily in the thick ascending loop of Henle. In the kidney, Ca2+ binds to the CaSR that leads to generation of an arachidonic acid metabolite that inhibits the potassium channel in the luminal membrane. Inhibition of K+ recycling reduces sodium chloride reabsorption via the Na-K-2Cl transporter, diminishing the luminal positive electrical gradient and therefore passive absorption of calcium and magnesium.

Front 6

Pathophysiology of Hypercalcemia

I. Review of Mineral Metabolism
(Response to hypocalcemia:)

Calcium Sensing Receptor (CaSR)

Net effect of activation of the CaSR by increased serum calcium is _________ PTH secretion and __________ urinary calcium reabsorption.

Back 6

decreased

decreased (increase excretion)

Front 7

Pathophysiology of Hypercalcemia

The same two hormones, PTH and vitamin D, which protect against hypocalcemia, can also protect against _____________.

Back 7

hypophosphatemia

Front 8

Pathophysiology of Hypercalcemia

B. Response to Hypophosphatemia

A reduction in the extracellular fluid phosphorus concentration results in enhanced conversion of ___________ to ______________ in the _________.

Back 8

25-hydroxcholecalciferol (25OH vitamin D3)

the active hormone, 1, 25 dihydroxycholecalcifierol(1,25 OH2D3)

kidney

Front 9

Pathophysiology of Hypercalcemia

B. Response to Hypophosphatemia

Hypophosphatemia => conversion of 25-hydroxcholecalciferol (25OH vitamin D3) to the active hormone, 1, 25 dihydroxycholecalcifierol (1,25 OH2D3) in the kidney => This results in several actions: (3)

Gut?
Bone?
Kidney?

Back 9

1) increased absorption of phosphorus, and calcium from the gut
2) increased bone resorption, with subsequent increased release of phosphorus, and calcium from the skeleton
3) increased reabsorption of phosphorus from the glomerular filtrate

Front 10

Pathophysiology of Hypercalcemia

B. Response to Hypophosphatemia

How is phosphate increased without hypercalcemia?

Back 10

Increased active 1,25 Vit. D will increase Ca and Phos. High Ca will result in low PTH. Vit. D and PTH have opposing actions in the kidney

- Vit.D enhances renal tubular reabsorption of phosphorus and depress renal calcium reabsorption (while PTH does opposite), resulting in a return of phosphorus concentration to normal with maintenance of the serum calcium level.


( Vit D:
(1) increased gut absorption of phosphorus and calcium
(2) bone resorption => release of phosphorus and calcium
(3)increased reabsorption of phosphorus from the glomerular filtrate *** Opposite of PTH!)

Front 11

Pathophysiology of Hypercalcemia

II. Hypercalcemia

Rare or Common?
Factitious causes?
Clinical manifestations are a reflection of ....... ?

Back 11

1. Common - 0.5-1.0% prevalence of increased TOTAL calcium

2. Almost always an elevation in the physiologically important ionized (free) calcium concentration.

-However, 40 to 45 percent of the calcium in serum is bound to protein, principally albumin. So changes in protein binding can cause an change in the serum total calcium concentration without any rise in the serum ionized calcium concentration.

-Altered pH can effect ionized calcium levels
•Alkaline pH reduces ionized calcium levels
•Acid pH increases ionized calcium

-Patients in whom this can occur include those with hyperalbuminemia due to severe dehydration and rare patients with multiple myeloma who have a calcium-binding paraprotein. This phenomenon is called pseudohypercalcemia (or factitious hypercalcemia), since the patient is really normocalcemic.

-Corrected serum calcium =
(Normal albumin-plasma albumin) x 0.8 + [Ca]


***Clinical manifestations are a reflection of ionized calcium.

Front 12

Pathophysiology of Hypercalcemia

II. Hypercalcemia

Clinical manifestations are a reflection of _________ calcium.

Symptoms are related to the degree and duration of ___________.

Clinical manifestations:
1. Renal ?
2. Gastrointestinal ?
3. Neuropsychiatric ?
4. Cardiovascular ?
5. Muscular ?
6. Rheumatologic ?

7. Asymptomatic?

Back 12

ionized

hypercalcemia


1. Renal dysfunction: hypercalcuria, nephrolithiasis, nephrocalciosis, renal insufficiency, nephrogenic diabetes insipidus

2. Gastrointestinal abnormalities: constipation, abdominal complaints, anorexia, rarely pancreatitis, nausea, peptic ulcer disease

3. Neuropsychiatric disturbances: anxiety, cognitive dysfunction, depression, confusion, hallucinations, and coma

4. Cardiovascular: shortened QT interval, hypertension, deposition of calcium in valves, myocardium, and coronary arteries

5. Muscular: muscle weakness

6. Rheumatologic: gout, pseudogout, chondrocalcinosis

7. Asymptomatic.

Front 13

Pathophysiology of Hypercalcemia

II. Hypercalcemia

Mechanisms of hypercalcemia

GI?
Bone?
Renal?
Diet?

Misc.

Back 13

1. Increased GI calcium absorption:
Vitamin D intoxication, granulomatous disorders, milk-alkali syndrome

2. Increased bone resorption:
Primary and secondary hyperparathyroidism, malignancy, hyperthyroidism, immobilization +/- Paget’s disease, Vitamin A intoxication
3. Decreased renal clearance:
Thiazide diuretics, milk-alkali syndrome, adrenal insufficiency
4. Increased calcium intake

5. Misc:
Lithium, pheochromocytoma, rhabdomyolysis, theophylline toxicity, familial benign hypocalcuric hypercalcemia

Front 14

Pathophysiology of Hypercalcemia

II. Hypercalcemia

Hormonal and non hormonal mediators of hypercalcemia? (4)

Back 14

1. Parathyroid hormone
2. Neoplasia
3. Vitamin D metabolites
4. Endocrinopathies: pheochromocytoma, hyperthyroidism, adrenal insufficiency

Front 15

Pathophysiology of Hypercalcemia

Most common cause of outpatient hypercalcemia?

Back 15

Primary Hyperparathyroidism

• 50,000 cases/year in U.S.
•25 cases per 100,000 general population
•over age 50: 360 cases per 100,000
•Female:Male 2:1

Front 16

Pathophysiology of Hypercalcemia

Primary Hyperparathyroidism

Clinical Manifestations?
Classical symptoms?

Back 16

Clinical Manifestations
•Often incidentally discovered
•80% of patients are asymptomatic at diagnosis

Classical symptoms:
“stones” (kidney stones)
“bones” (low bone mass or rarely osteitis fibrosa cystica),
“abdominal groans” (peptic ulcer disease, pancreatitis, constipation),
“moans” (generalized fatigue, weakness, arthralgia, myalgias)
“psychic overtone” (depression, lethargy, poor concentration)

Front 17

Pathophysiology of Hypercalcemia

Primary Hyperparathyroidism

Pathology?

Back 17

Adenoma 80%
Double adenoma 5%
Hyperplasia 15% (half have MEN1 or 2a)
Cancer 1-2%

Front 18

Pathophysiology of Hypercalcemia

Primary Hyperparathyroidism

Biochemical Profile:
(1) Hallmark?
(2) Blood phosphate?
(3) 1,25 dihydroxyvitamin D3
(4) PTH
(5) AlkPhos
(6) Urine Ca and phosphate

Back 18

1. Hypercalcemia is the hallmark
2. Hypophosphatemia or low normal phosphate
3. Increased levels of circulating 1,25 dihydroxyvitamin D3
4. Elevated or inappropriately normal PTH
5. Increased alkaline phosphatase
6. Hypercalciuria and hyperphosphaturia

Front 19

Pathophysiology of Hypercalcemia

Primary Hyperparathyroidism

Why does excess PTH result in hypercalcemia? (3 main organs?)

Back 19

1. Kidney
• ↑ tubular reabsorption of calcium
• ↑ cyclic AMP (via PTH binding to PTH/PTHrP receptor and stimulating adenylyl cyclase and cAMP)
• ↑ 1,25(OH)2D production
• ↑ urine Phosphorus
2. Bone
• ↑ Activation of osteoclasts with increased bone turn over
• ↑ Calcium (and PO4) release
3. Gut
• ↑ calcium and phosphorus reabsorption via increased 1,25(OH)2D3

Front 20

Pathophysiology of Hypercalcemia

Primary Hyperparathyroidism

Rb gene and HRPT2 gene defects?

deletions on chromosome 11 including the location of the MENIN gene?

Back 20

Parathyroid carcinomas frequently have Rb gene and HRPT2 gene defects


Parathyroid adenomas and hyperplasia are monoclonal tumors; large tumors frequently show deletions on chromosome 11 including the location of the MENIN gene.

Front 21

Pathophysiology of Hypercalcemia

Primary Hyperparathyroidism

Pathophysiology
PTH regulation?
What causes parathyroid adenomas?
Parathyroid carcinomas?

Back 21

1. Excessive secretion of PTH with loss of normal inhibition of PTH secretion by increase in serum calcium.
2. Parathyroid adenomas and hyperplasia are monoclonal tumors; large tumors frequently show deletions on chromosome 11 including the location of the MENIN gene.
3. Parathyroid carcinomas frequently have Rb gene and HRPT2 gene defects

Front 22

Pathophysiology of Hypercalcemia

Primary Hyperparathyroidism

Familial Hyperparathyroid Syndromes:
1. Multiple Endocrine Neoplasia 1:

Back 22

Parathyroids, Pituitary, Pancreas (P3); gene defect has been localized to the long arm of chromosome 11 and cloned: MENIN gene thought to function as a tumor suppressor gene.

Presentation: Hyperparathyroidism!

Front 23

Pathophysiology of Hypercalcemia

Primary Hyperparathyroidism

Familial Hyperparathyroid Syndromes:

Multiple Endocrine Neoplasia 2A

2B?

Back 23

Medullary thyroid cancer, parathyroids, pheochromocytoma;

gene defect is an activating mutation of the "ret" oncogene, a tyrosine kinase, at codons for cysteines in exon 10 or 11. The RET proto-oncogene encodes a transmembrane receptor with tyrosine kinase activity. Germline mutations in RET are responsible for a number of inherited diseases. These include the dominantly inherited cancer syndromes multiple endocrine neoplasia types 2A and 2B (MEN 2A and MEN 2B) and familial medullary thyroid carcinoma (FMTC), as well as some cases of familial Hirschsprung disease (HSCR1). RET mutations in HSCR1 (exons 2-6) have been shown to cause a loss of RET function, while the cancer syndromes result in RET oncogenic activation.


Presentation: Medullary thyroid cancer


2B: also Ret proto-oncogene but no parathyroid involvement.

Front 24

Pathophysiology of Hypercalcemia

Primary Hyperparathyroidism

Familial Hyperparathyroid Syndromes:

Multiple Familial Benign Hypocalciuric Hypercalcemia:

a. Clinical manifestation?
b. Gene?
c. Biochemical Profile?

Back 24

a. asymptomatic hypercalcemia with PTH normal / slightly elevated; increased renal reabsorption of calcium; generally benign. Urinary calcium excretion and Ca/Creatinine clearance ratio are much lower than in primary hyperparathyroidism or other causes of hypercalcemia.


b. inactivating mutation in the membrane-bound calcium-sensing receptor (CaSR) expressed on parathyroid cells and renal tubules.
Homozygous CaSR inactivating mutations result in neonatal severe hyperparathryoidism, which is potentially lethal and requires total parathyroidectomy. Inactivating mutations in the CaSR make the parathyroid and distal tubule of the nephron insensitive to elevations in serum calcium and thus PTH synthesis and secretion continue despite hypercalcemia. Additionally, calcium reabsorption in the distal renal tubule continues despite elevated serum calcium levels. Gene penetrance is high and screening family members for hypercalcemia is a reliable way to make the diagnosis of FHH.

c. Biochemical Profile of FHH: hypercalcemia, hypophosphatemia, low urine calcium, elevated or inappropriately normal PTH.

Front 25

Pathophysiology of Hypercalcemia

IV. MALIGNANCY ASSOCIATED HYPERCALCEMIA

Asymptomatic?

Pathogenetic Classification? (4)

Back 25

•Incidence: 15 cases per 100,000
•Clinical presentation: Generally symptomatic
•Malignancy generally obvious
•Calcium very high (>14 mg/dl) and duration short


1. Local osteolytic hypercalcemia
-Direct invasion
-Cytokine-mediated

2.Humoral hypercalcemia
-PTHrp [Parathyroid hormone-related protein is a family of protein hormones produced by most if not all tissues in the body. A segment of PHRH is closely related to parathyroid hormone, and hence its name, but PHRH peptides have a much broader spectrum of effects. PHRH was discovered as a protein secreted by certain tumors that caused hypercalcemia (elevated blood calcium levels) and other effects. It was soon shown that the uncontrolled secretion of PHRH by many tumor cells induces hypercalcemia by stimulating resorption of calcium from bone and suppressing calcium loss in urine, similar to what is seen with hyperparathyroidism.]

3. Very rarely (reportable cases) ectopic PTH production

4. Ectopic 1α OHase activity in lymphomas

Front 26

Pathophysiology of Hypercalcemia

IV. MALIGNANCY ASSOCIATED HYPERCALCEMIA

MECHANISM?

_________, _______ _______, and _________ promote the differentiation and activation of ___________ which ______ bone and ______ calcium;

__________ bone formation ("uncoupling" of normal cycle of bone resorption-bone formation) with _________ skeletal uptake of calcium.

Back 26

Cytokines, growth factors, and PTHrP
osteoclasts which resorb bone and liberate calcium from bone;

decreased bone formation with decreased skeletal uptake of calcium.

Front 27

Pathophysiology of Hypercalcemia

IV. MALIGNANCY ASSOCIATED HYPERCALCEMIA

Hematologic Cancers Metastatic to Bone

What happens in bone?
Important factors?
Parathyroid function?
Urine calcium?

Back 27

1. Increased osteoclastic activation with extensive bone destruction.

2."Osteoclast activating factor" (OAF). A FAMILY of lymphokines such as Interleukins; Tumor Necrosis Factor, alpha (TNFα); lymphotoxin; prostaglandin E2, TGFβ

3. HYPERCALCEMIA SUPPRESSES PARATHYROID FUNCTION: ↓ PTH ↓ 1,25(OH)2D
↓ urine cAMP (PTH receptor not activated, PTH is low)
↑ fractional calcium excretion (elevated urinary calcium)

Front 28

Pathophysiology of Hypercalcemia

IV. MALIGNANCY ASSOCIATED HYPERCALCEMIA

Hematologic Cancers II (Tumor cells not in bone) - Lymphomas, particularly histiocytic type

What do they do?
Important factors?
Parathyroid function?
Urine calcium?
Phosphorus?

Back 28

1.↑ ectopic conversion of 25(OH)2D to 1,25(OH)2D in lymphoma

2.↑ 1,25(OH)2D causes increased calcium resorption from bone and GI absorption
4.HYPERCALCEMIA SUPPRESSES PARATHYROID FUNCTION
↑1,25(OH)2D
↓PTH
↓ urine cAMP
↑ fractional calcium excretion
↑ or normal phosphorus

Front 29

Pathophysiology of Hypercalcemia

IV. MALIGNANCY ASSOCIATED HYPERCALCEMIA

Solid tumors with bone metastases: Local osteolytic hypercalcemia

What do they do?
Parathyroid function?
Urine calcium?

Back 29

1. Bone destruction by direct tumor cell invasion

2.Tumor cells can release factors locally (e.g., PGE2) to activate osteoclasts

3. HYPERCALCEMIA SUPPRESSES PARATHYROID FUNCTION:

↓ PTH
↓1,25(OH)2D
↓ urine cAMP
↑ fractional calcium excretion

Front 30

Pathophysiology of Hypercalcemia

IV. MALIGNANCY ASSOCIATED HYPERCALCEMIA

HUMORAL HYPERCALCEMIA OF MALIGNANCY: "HHM"

What is it?
Cancer types?
Urine calcium?

Back 30

Solid tumors without bone metastases

1.No evidence of direct bone invasion by tumor cells
2.Tumors secrete "factors" that markedly increase bone resorption

a. "PTH related protein" a unique protein produced by a gene on human chromosome 12; most commonly contains 141 amino acids, but due to alternative processing of the primary mRNA transcript may have 139 or 173 amino acids; first 13 amino acids show high structural homology to PTH; binds to PTH receptors in bone and kidney and activates adenylate cyclase; is the major calciotropic hormone of the fetus but in adults is normally expressed at very low levels in keratinocytes and selected other cells.

b. Typically over-expressed in squamous cell cancers, but also in kidney and breast cancer. The PTH-related protein increases urine cAMP because it bind to the PTH receptor and activates adenylyl cyclase and subsequently cAMP; surprisingly, levels of 1,25(OH)2D are not elevated, PTH levels are suppressed. Urine calcium is markedly elevated.

Front 31

Pathophysiology of Hypercalcemia

IV. MALIGNANCY ASSOCIATED HYPERCALCEMIA

Summary:

For these diseases, what is the mechanism, action, biochemical profile of the hypercalcemia?

Multiple Myeloma
Hematologic malignancies

Back 31

Local Osteolytic Hypercalcemia

Osteoclast activating cytokines released from tumor

↓PTH
↓1,25 OH2 D3
↓uCAMP
↑uCA

Front 32

Pathophysiology of Hypercalcemia

IV. MALIGNANCY ASSOCIATED HYPERCALCEMIA

Summary:

For these diseases, what is the mechanism, action, biochemical profile of the hypercalcemia?

Breast cancer
Prostate cancer
Solid tumors

Back 32

Local Osteolytic Hypercalcemia

Direct tumor invasion
Release of local cytokines from bone

↓PTH
↓1,25 OH2 D3
↓uCAMP
↑uCA

Front 33

Pathophysiology of Hypercalcemia

IV. MALIGNANCY ASSOCIATED HYPERCALCEMIA

Summary:

For these diseases, what is the mechanism, action, biochemical profile of the hypercalcemia?

Squamous, Renal cell, and breast cancer

Back 33

PTHrp: “Humoral hypercalcemia of malignancy”

Activates PTH/PTHrp receptor

↓PTH
↓1,25 OH2 D3
↑↑uCAMP
↑PTHrp
↑uCA
↓Phos

Front 34

Pathophysiology of Hypercalcemia

IV. MALIGNANCY ASSOCIATED HYPERCALCEMIA

Summary:

For these diseases, what is the mechanism, action, biochemical profile of the hypercalcemia?

Lymphoma
Granulomatous Disease

Back 34

1,25 OH2 D3
(↑ ectopic conversion from 25(OH)2D )

GI calcium and phos absorption

↓PTH
↑1,25 OH2 D3
↑ Phos
↓uCAMP
↑uCA

Front 35

Pathophysiology of Hypercalcemia

V. VITAMIN D INTOXICATION

Normal Synthesis?

Back 35

Whether it is made in the skin or ingested, vitamin D3 (cholecalciferol) is then hydroxylated in the liver to 25-hydroxycholecalciferol (25(OH)D3 or calcidiol) by the enzyme 25-hydroxylase produced by hepatocytes, and stored until it is needed.

25-hydroxycholecalciferol is further hydroxylated in the kidneys by the enzyme 1α-hydroxylase, into two dihydroxylated metabolites, the main biologically active hormone 1,25-dihydroxycholecalciferol (1,25(OH)2D3 or calcitriol) and 24R,25(OH)2D3. This conversion occurs in a tightly regulated fashion.

Front 36

Pathophysiology of Hypercalcemia

V. VITAMIN D INTOXICATION

EXOGENOUS?

Back 36

It does occur due to increased consumption of vitamin D - leading to unregulated increase in 25(OH)D levels; PTH and 1,25(OH)2D are normal or suppressed.

Front 37

Pathophysiology of Hypercalcemia

V. VITAMIN D INTOXICATION

ENDOGENOUS
Causes?
Mechanism?
Tx?

Back 37

Sarcoid is prototype for granulomatous diseases, but tuberculosis, coccidiomycosis, cytomegalovirus, histoplasmosis, silicone, and candidiasis related granulomas may also cause hypercalcemia.

1. Mechanism: Lymphocytes of granulomas exhibit increased activity of an unregulated ectopic 1α hydroxylase enzyme with conversion of 25(OH)D to 1,25(OH)2D;

2.In contrast to normal (eutopic) renal 1α hydroxylase, where activity is tightly regulated (PTH increases activity and PO4 decreases activity), the ectopic enzyme is largely substrate [i.e., 25(OH)D] dependent.

3. Patients are sensitive to small increases in dietary intake of vitamin D and sunlight (i.e., solar related production of vitamin D).

Front 38

Pathophysiology of Hypercalcemia

V. VITAMIN D INTOXICATION

Glucocorticoid responsive?

Back 38

Yes - give prednisone tx for patients with high endogenous calcitriol production due to sarcoid, etc.

Front 39

Hypercalcemia: Differential Diagnosis

Back 39

Increased GI calcium absorption
Increased Bone Resorption
Decreased Renal Clearance
Increased calcium intake
Medications: Li, thiazides, theophylline
Endocrinopathies

Front 40

Hypercalcemia of Malignancy: Common?

Back 40

Complicates 10-20% of cancer
Symptomatic, Severe hypercalcemia
Malignancy usually obvious
Acute onset

Front 41

Hypercalcemia of Malignancy:

Urinary cAMP high in one type of malignancy?

Back 41

Humoral Hypercalcemia of Malignancy: PTHrp => Binds PTH receptor and activates adenylyl cyclase => High uCAMP

(also high in Primary Hyperparathyroidism—excess PTH production)

(NOT in Vitamin D excess-granulomatous disorders)

Front 42

Pathophysiology of Hypocalcemia


REMINDER: True hypocalcemia is associated with reduced levels of ________ ________. Don’t be fooled by low serum ________ levels that result in reduced TOTAL calcium concentration.

Back 42

ionized calcium

albumin

Front 43

Pathophysiology of Hypocalcemia

Hypocalcemia results from: (5)

Back 43

A. Deficient secretion of PTH

B. Deficient action of PTH (PTH resistance)

C. Deficient vitamin D supply or activation

D. Deficient action of Vitamin D (1,25 (OH)2 D resistance)

E. Chelation of calcium by bone or plasma

Front 44

Pathophysiology of Hypocalcemia


II. Causes of Hypocalcemia
A. Deficient secretion of PTH (4)
B. Deficient action of PTH (1)
C. Deficient vitamin D supply or activation (6)
D. Deficient action of Vitamin D (1)
E. Chelation of calcium by bone or plasma (3)

F. Misc (4)

Back 44

A. Decreased PTH Secretion
Parathyroid agenesis
Parathyroid destruction
Autoimmune
Reduced parathyroid function

B. Decreased PTH action
(parathyroid hormone resistance): Pseudohypoparathyroidism
C. Deficient Vitamin D supply and metabolism
Nutritional Deficiency
Lack of sunlight
GI malabsorption
Acute or chronic renal failure—1α hydroxylase deficient
Liver disease-25 hydroxylase deficient
Genetic mutations in 1α hydroxylase gene

D. Deficient Vitamin D action
Vitamin D receptor defects--1,25(OH)2Vitamin D3 resistance

E. Chelation
Medications
1. Plasma Chelators: phosphate, citrated blood products
2. Bone Chelators: Inhibitors of Bone resorption: bisphosphonates, gallium nitrate, calcitonin, plicamycin, cisplatinum, doxorubicin
3. Altered Vitamin D metabolism: anticonvulsants

F. Miscellaneous
Pancreatitis, Rhabdomyolysis, Tumor lysis, Acute severe illness

Front 45

Pathophysiology of Hypocalcemia


III. Clinical Manifestations

Severity dependent on (3)?

Main systems affected (4)?

Chronic hypocalcemia (5)

Back 45

• Severity dependent upon ionized calcium level, acuteness of onset, and duration of hypocalcemia


•Neuromuscular: tetany, Chvostek’s, Trousseau’s, parathesias, seizures, muscle cramps, spasms, or weakness and papilledema
•Psychiatric: anxiety, irritability, psychosis, depression, dementia, coma
•Respiratory: laryngeal spasm, bronchospasm, muscle fatigue
•Cardiovascular: prolonged QT interval, arrhythmia, heart failure, hypotension


•Chronic hypocalcemia: Dental abnormalities, ectodermal changes, calcified basal ganglia, cataracts, extrapyramidal disorders

Front 46

Pathophysiology of Hypocalcemia

IV. Hypocalcemia: Vitamin D defects
A. Vitamin D Synthesis
Deficiency of vitamin D, 1,25(OH)2D, may cause both ___calcemia and ____phosphatemia.

Synthesis of the active form of vitamin D (1,25(OH)2D3) requires adequate ___ absorption, intact ___ and adequate ___ exposure, normal ____ and ____ function for the appropriate hydroxylations. In addition, the target organs for 1,25(OH)2D3 must have a _____________.

Back 46

hypo, hypo

GI absorption, intact skin and adequate sun exposure, normal liver and kidney function

functional vitamin D receptor (see figure below).

Front 47

Pathophysiology of Hypocalcemia

IV. Hypocalcemia: Vitamin D defects

Functions of 1,25(OH)2D
GI? (1)
Bone? (3)
Kidney (1)
Marrow? Muscle?

Back 47

•Promote enterocyte differentiation & GI calcium and phosphate absorption

•Regulation of osteoblast (bone building cells) function

•Promotes mineralization of osteoid

•Promote PTH induced osteoclast (bone resorbing cells) mediated bone resorption

•Promotes calcium and phosphorus reabsorption from the kidney

•Regulation of hematopoietic and muscle function

Front 48

Pathophysiology of Hypocalcemia

IV. Hypocalcemia: Vitamin D defects

Disorders Associated with Vitamin D deficiency (7) + meds

Back 48

Nutritional Deficiency
Reduced cutaneous production
Gastrointestinal malabsorption
Hepatic disease
Renal disease
Vitamin D receptor defects
Vitamin D dependent rickets (1α hydroxylase deficiency)

Medications: Anticonvulsive therapy, INH, theophylline, rifampin

Front 49

Pathophysiology of Hypocalcemia


1α hydroxylase deficiency

Back 49

Vitamin D dependent rickets

Front 50

Pathophysiology of Hypocalcemia

IV. Hypocalcemia: Vitamin D defects

Biochemical Profile:
• PTH
• Serum calcium
• Serum phosphate
• Urine calcium
• Urinary cAMP
• 25 (OH) D
• 1,25(OH)2D
• Vitamin D levels in vitamin D resistant rickets (vitamin D receptor defects)
• Alkaline phosphatase

Back 50

• Increased PTH
• Decreased serum calcium
• Decreased serum phosphate
• Decrease urine calcium
• Increase urinary cAMP (through action of PTH on the PTH receptor in the kidney)
• Low 25 (OH) D (in nutritional deficiency, malabsoprtion, liver disease, cutaneous disorders)
• Low 1,25(OH)2D ( in renal disease)
• Vitamin D levels are normal or elevated in vitamin D resistant rickets ( vitamin D receptor defects)
• Elevated alkaline phosphatase (osteoblasts are active making osteoid but there is lack of mineral)

Front 51

Pathophysiology of Hypocalcemia

IV. Hypocalcemia: Vitamin D defects

Biochemical Profile: In vitamin D deficiency or vitamin D insensitivity, absorption of calcium and phosphorus from the gut is __________. 1,25 (OH)2D is also a potent stimulator of bone _________, and its absence may _______ the availability of calcium from bone. Because the parathyroid glands are intact in vitamin D deficient states, hypocalcemia induces secondary ____________ and renal phosphate clearance is _________. Thus, hypocalcemia in vitamin D deficiency results from decreased intestinal absorption of calcium and limited availability of calcium from bone despite secondary hyperparathyroidism; characteristically it is accompanied by hypophosphatemia.

Back 51

markedly impaired

resorption, decrease

hyperparathyroidism, enhanced

Front 52

Pathophysiology of Hypocalcemia

IV. Hypocalcemia: Vitamin D defects
E. Clinical Features: Signs and Symptoms

Called in ___________ adults and _________ in children.

Signs and Symptoms (7)

Back 52

osteomalacia, rickets

•Muscle weakness
•Diffuse skeletal pain worsening with activity
•Pain in lower back and hips
•Fractures
•Hypotonia in children
•Bone and cartilage defects and bony deformity-when bone mineralization is impaired in children it affects both the growth plate and the growing bone, producing rickets. In adults, who have no growth plate, only growing bone is affected producing osteomalacia.
•Tetany

Front 53

Pathophysiology of Hypocalcemia

IV. Hypocalcemia: Vitamin D defects
E. Radiographic findings?

Back 53

Radiographic findings: Looser zones, codfish vertebrae, metaphyseal fraying, bowing of lower extremities

Front 54

Pathophysiology of Hypocalcemia

V. Hypocalcemia: Hypoparathyroidism

Bone resorption and release of calcium ions from skeletal stores is _________. Renal tubular reabsorption of calcium is _________, but because of hypocalcemia and low filtered load, urinary calcium is ___. In the absence of PTH action, urinary clearance of phosphate is __________, and _____phosphatemia is common.

Effect on Vit.D?

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diminished

decreased, low

decreased, hyper

The defiency of PTH and hyperphosphatemia impair renal production of 1,25(OH)2D. The low circulating 1,25(OH)2D results in reduced intestinal calcium absorption as well as decreased bone resorption.

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Pathophysiology of Hypocalcemia

V. Hypocalcemia: Hypoparathyroidism

most common reason for hypoparathyroidism?

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Surgery: most common reason for hypoparathyroidism. Most commonly associated with thyroid surgery or other anterior neck surgery

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Pathophysiology of Hypocalcemia

V. Hypocalcemia: Hypoparathyroidism

A. Destruction (3)

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1. Surgery: most common reason for hypoparathyroidism. Most commonly associated with thyroid surgery or other anterior neck surgery
2. Irradiation
3. Infiltration by metastasis or systemic disease: (Hemachromatosis, sacroid, Wilson’s disease, amyloidosis)

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Pathophysiology of Hypocalcemia

V. Hypocalcemia: Hypoparathyroidism

B.Autoimmune ?

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1. Autoimmune Polyglandular Syndrome Type 1 (recessive, childhood, "HAM", AIRE gene (autoimmune reg), Now called APECED)

2. Isolated autoimmune destruction

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Pathophysiology of Hypocalcemia

V. Hypocalcemia: Hypoparathyroidism

Autoimmune Polyglandular Syndrome Type 1
a. Inheritance?
b. Classic triad?
c. Associations?
d. New name?
e. Gene?

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a. Autosomal recessive inheritance pattern usually presents in childhood

b. Classic triad: hypoparathyroidism, adrenal insufficiency, mucocutaneous candidiasis (HAM)

c. May be associated with other autoimmune endocrinopathies: type 1 diabetes, hypogonadism,thyroiditis,ectodermal dysplasia, pernicious anemia, autoimmune hepatitis, malabsorption (celiac disease).

d. Newer name APECED (Autoimmune Polyglandular Candidiasis Ectodermal Dystrophy Syndrome)

e. AIRE gene mutations (autoimmune regulator gene) on chromosome 21q22.3 encodes a transcription factor. It is expressed in immunologically related tissues, especially the thymus, and functional loss leads to the breakdown of immune tolerance to organ-specific self-antigens.

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Pathophysiology of Hypocalcemia

V. Hypocalcemia: Hypoparathyroidism

D.Reduced Parathyroid hormone secretion

Autosomal Dominant Hypocalcemia:
Mutation?
Net effect?
Urine calcium?

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Impaired Secretion of PTH Due to Activating Mutation of the CaSR


[RECALL: G protein-coupled hepathelical receptor on the surface of parathyroid cells and in renal tubule cells. CaSR permits variations in serum calcium concentrations to be sensed by the parathyroid glands leading to the desired changes in PTH concentration.]


Net effect of activation of the CaSR is decreased PTH secretion and decrease urinary calcium reabsorption (increase excretion.


patients with activating mutations of the CaSR gene manifest hypercalcuria (elevated urinary calcium excretion) despite reduced serum calcium levels that lead to a low renal filtered load of calcium. These patients have hypercalciuric hypocalcemia—the opposite of Familial Hypocalciuric hypercalcemia that arises from inactivating mutation in the CaSR.

1. preproPTH gene defects can lead to isolated hypoparathyroidism.
2. Hypomagnesemia-impairs mechanism for PTH secretion
4. Hypermagnesemia-inhibits PTH secretion by interacting with the CaSR.

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Pathophysiology of Hypocalcemia

V. Hypocalcemia: Hypoparathyroidism
E. Clinical Manifestations of prolonged hypocalcemia and hyperphosphatemia

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•Subcapsular cataracts
•Basal ganglion calcification
•Long standing hypocalcemia due to hypoparathyroidism
i.Ectodermal findings: dry skin, coarse hair, brittle nails,
ii.Dental and enamel hypoplasia, absence of adult teeth

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Pathophysiology of Hypocalcemia

V. Hypocalcemia: Hypoparathyroidism
F.Biochemical Profile

•____calcemia
•____phosphatemia
•____ PTH
•____ 1,25 (OH)2D
•____ urine calcium (except in autosomal dominant hypocalcemia)
•____ urinary cAMP
•____ 25(OH) D
•____ urinary phosphate reabsorption

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•Hypocalcemia
•Hyperphosphatemia
•Low PTH
•Low normal 1,25 (OH)2D
•Relatively low urine calcium (except in autosomal dominant hypocalcemia)
•Low urinary cAMP
•Normal 25(OH) D
•Increased urinary phosphate reabsorption

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Pathophysiology of Hypocalcemia

Pseudohypoparathyroidism - what is it?

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describes a group of disorders characterized by:
(1) biochemical hypoparathyroidism (i.e. hypocalcemia + hyperphosphatemia),
(2) increased secretion of PTH, and
(3) target tissue unresponsiveness to the biological actions of PTH.

Thus, biochemical hypoparathyroid in PHP is due to PTH resistance of target tissues, bone and kidney rather than PTH deficiency.

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Pathophysiology of Hypocalcemia

VI. Hypocalcemia: Parathyroid Hormone Resistance

B. Pathophysiology - Kidney

Site of defect?
Other affected signals?

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•Resistance of the kidney to the biological actions of PTH
•PTH-receptor-adenylyl cyclase complex is the site of defect (heterozygous inactivating mutations in the gene encoding the alpha subunit of guaninie-nucleotide stimulatory protein (Gsα), GNAS).

•The initial event in PTH action is binding to the PTH/PTHrP receptor on the plasma membrane of target cells. The PTH/PTHrP receptor is coupled to heterotrimeric guanine nucleotide binding regulatory proteins (G proteins) to signal intracellular downstream effectors. These cascade of effectors exert the biological effects of PTH. The best characterized mediator of PTH action is cAMP which activated protein kinase A.

•The stimulatory G protein Gs couples many seven transmembrane receptor to adenylyl cyclase and down stream receptors. This is why resistance to multiple hormones (PTH, TSH, LH, GHRH) is observed in individual with PHP 1a.

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Pathophysiology of Hypocalcemia

VI. Hypocalcemia: Parathyroid Hormone Resistance

In PHP1a and PPHP, patients have a constellation of developmental and skeletal defects termed _________. These features include including ....

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Albright’s Hereditary Osteodystrophy, AHO

short stature, obesity, round facies, brachymetacarpia, subcutaneous ossification and mental deficiency.

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Pathophysiology of Hypocalcemia

VI. Hypocalcemia: Parathyroid Hormone Resistance

What is the difference between Pseudohypoparathyroidism (PHP) and Pseudo-pseudohypoparathyrodism (PHPP)?

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Classification of PHP type 1 is based on the presence of AHO and hormone resistance. Individuals with PHP 1a and PPHP have AHO. The feature that distinguishes PHP1a from PPHP is the presence or absence of hormone resistance. Individuals with PPHP and PHP1a may segregate in the same family with the same GNAS mutation. Whether an individual has PPHP or PHP1a is determined by which GNAS allele bears the mutation. If the mutation is on the maternal allele, PHP 1a is manifest. If the mutation is on the paternal allele then clinical manifestation will be PPHP. PHP1b is a distinct syndrome and individuals with PHP1b and PHP 1a do not segregate in the same family. Patients with PHP 1b lack features of AHO and have resistance that is restricted to PTH and other imprinted tissues.

• This difference in clinical phenotype that is observed based on the parental origin of the gene mutation arises because GNAS is an imprinted gene.

• Imprinting is an epigenetic marking of a gene based on the parental origin that results in monoallelic expression. Most genes are expressed in a biallelic fashion, one transcript from the maternal allele and one from the paternal allele. In imprinted genes, one allele is silenced usually through methylation of CpG islands in or near the gene.

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Pathophysiology of Hypocalcemia

VI. Hypocalcemia: Parathyroid Hormone Resistance

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PHP is a heterogeneous group of disorders characterized by hormone resistance the hallmark of which is PTH resistance. Typically they present with biochemical hypoparathyroidism that is due to resistance to parathyroid hormone rather than PTH deficiency. \
In PHP 1a, patients have a constellation of developmental and skeletal defects termed AHO. These features include including short stature, obesity, round facies, brachymetacarpia, subcutaneous ossification and mental deficiency.
There is marked phenotypic variability even within families


Within families with PHP, affected individuals express the AHO phenotype but only some display multiple hormone resistance.
Individuals with PHP 1a, have AHO and multiple hormone resistance including to PTH, TSH. While patients with AHO only are termed PPHP.
Whether the PHP 1a or the PPHP phenotype is manifested depends on the parental origin of the genetic mutation. PHP 1a results from maternal inheritance whereas PPHP results from paternal inheritance.
In each instance, the levels of Gsa in erthryocyte membranes is reduced.

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Pathophysiology of Hypocalcemia

AIRE : Autoimmune Regulator Gene

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Encodes a transcription factor
Expressed in immunologically related tissues such as thymus
Functional loss leads to breakdown of immune tolerance to organ specific antigens


Autoimmune Hypoparathyroidism
Hypoparathyroidism Adrenal insufficiency
Mucocutaneous candidiasis

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Screening for Vitamin D Deficiency

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25(OH) D is the best measure
Half-life in circulation 2 weeks
Concentration ng/ml

1,25(OH)2D is the active form
Half life is 4 hours
Concentration 1000 fold less than 25(OH)D
Regulated by PTH

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Summary of PHP
PHP1a vs. PPHP

Ca
Phos
PTH
UCAMP (after PTH)
Other hormone resistance
AHO

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PHP1a

Ca low
Phos high
PTH high
UCAMP (after PTH) blunted
Other hormone resistance yes
AHO yes


PPHP
Ca normal
Phos normal
PTH normal
UCAMP (after PTH) normal
Other hormone resistance no
AHO yes

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Childhood Rickets as a Manifestation of Nutritional Deficiency - 3

Specific Populations at Risk of Rickets - 3

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Vitamin D deficiency
Calcium deficiency
Phosphorous deficiency


Dark-skinned infants
Urban centers
Polar latitudes

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PTH effect on serum calcium?

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Raising.

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Diagnosing PHP?

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cAMP mediates many of the actions of PTH on kidney and bone. Administration of PTH to normal subjects leads to a significant increase in urinary excretion of nephrogenous cAMP. The PTH infusion test is the most reliable test and allows the distinction between several variant of PHP. Patients with type I (PHP 1a and PHP 1b) fail to show the appropriate increase in urinary cAMP and the phosphaturic response to PTH. Patients with PPHP exhibit normal urinary cAMP in response to PTH infusion.

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Small Group

-72 year old white woman
-multiple rib fractures
-polyuria, nocturia, constipation, and poor appetite
-High serum Ca, Low Phos


1. What is the most likely diagnosis? What laboratory test would confirm your diagnosis?
2. What are other possible causes of hypercalcemia in this patient? Specifically, what other cause(s) of hypercalcemia does one need to consider in this patient with a pathologic fracture?
3. Which symptoms might be attributed to hypercalcemia in this patient?
4. What laboratory and radiological tests are helpful in the evaluation of hypercalcemia?
5. What are the effects of PTH on bone? on kidney? on the gastrointestinal tract?
6. What is the possible significance of the patient's family history? Would your clinical diagnosis be changed if you knew that the onset of hypercalcemia was 2 months ago? 35 years ago?
7. What are the therapeutic options?

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Answers:
1. Primary hyperparathyroidism
Most common between ages 30 70
female: male 2:1
In one large review, single adenoma 85%
hyperplasia 14%
carcinoma 1%

Best laboratory test: serum PTH; is elevated in over 95% of patients with 1° HP.
The osteoporosis may be related to chronic estrogen deficiency, age, and primary hyperparathyroidism.

2. Other etiologies include:

Neoplastic diseases, particularly worry about multiple myeloma with mild renal insufficiency, proteinuria, and anemia. Neoplasia would be most ominous, particularly if onset of hypercalcemia is recent. Elevated PTH excludes this diagnosis with 99% certainty.
thyrotoxicosis
adrenal insufficiency
pheochromocytoma
thiazide diuretics
milk alkali or calcium gluttony (she is not taking enough Tums, each regular tablet contains 200 mg of elemental calcium)
sarcoidosis, other granulomatous diseases
immobilization
vitamin D toxicity


3. Constipation, anorexia, polyuria, nocturia, memory loss, muscle weakness and bone pains are all associated with hypercalcemia. Mental disturbances may be subtle and when present do not necessarily correspond to level of calcium. Polyuria and nocturia can result from nephrogenic diabetes insipidus.

Other associated manifestations: renal colic
peptic ulcer
hypertension
pancreatitis

4. The most important test is iPTH; secretion of PTH is inversely regulated by the level of ionized calcium. In primary hyperparathyroidism, iPTH is inappropriately elevated; PTH is suppressed in all other causes of hypercalcemia (e.g. malignancy). Other lab tests include PTHrP level, which would be elevated in humoral hypercalcemia of malignancy.

Urinary cyclic AMP is a good indicator of PTH action on renal tubules. Normally, total urinary cAMP reflects the filtered cAMP from the extra cellular pool and the nephrogenous component of cAMP (about 50%) which results from the action of PTH on the proximal tubules. Because the filtered portion is relatively constant, changes in urinary cAMP reflect changes of PTH action on the kidney. Nephrogenous cAMP is also increased by malignancies that produce PTH related peptide, so is of no discriminatory value in most cases.

25(OH)D is elevated in vitamin D intoxication and 1,25(OH)2D is elevated in primary hyperparathyroidism, sarcoid, and other granulomatous diseases. 24 hour urine calcium is most elevated in malignancy, sarcoid, vitamin D intoxication; elevated in about one third to one half of patients with primary hyperparathyroidism; and frankly low in patients with familial hypocalciuric hypercalcemia.

X-rays in primary hyperparathyroidism are typically normal or show generalized decrease in bone density; rarely show salt-and-pepper skull, subperiosteal resorption of cortical bone in fingers and distal clavicles. Sarcoid typically has abnormal chest x-ray.

A third useful measurement is the Tubular Reabsorption of Phosphate (TRP). Normally 85-95% of filtered phosphate is reabsorbed. Tubular reabsorption of phosphate can also be expressed as the TmP/GFR (tubular maximal phosphate threshold corrected for GFR) which is about 3 mg/dl. Increasing PTH (or PTHrP) lowers TmP/GFR and TRP.

5. Long term effects of parathyroid hormone on bone appear to be result from inhibition of osteoblasts and the formation of a new pool of osteoclasts with involvement of larger bone surface for resorption. Cortical bone resorption.

The classical bone disease of hyperparathyroidism is osteitis fibrosa cystica. Histologically, this consists of increased bone formation and reabsorption with an increase in active osteoclasts, loss of trabecular and cortical bone, increase in unmineralized bone, and extensive fibrosis. Clinically, it can be characterized by bone pain, pathological fractures of lone bones and crush fractures of spine, skeletal deformities. Radiographically, specific findings are subperiosteal bone resorption of middle phalanges or distal clavicle. Moth eaten pattern on the skull, bone cysts, or brown tumors.

PTH acts on kidney to decrease phosphate reabsorption and increase calcium reabsorption; also increases conversion of 25-hydroxy vitamin D to 1,25-dihydroxy vitamin D. No direct actions of PTH on gut, but leads indirectly to increased absorption of calcium and phosphorous through increased 1,25-dihydroxy vitamin D.

6. Primary hyperparathyroidism due to multi gland hyperplasia may occur in association with other endocrine tumors in the familial MEN I (parathyroid, pituitary, pancreas) and MEN 2 (medullary thyroid carcinoma, pheochromocytoma, parathyroid) syndromes. Recent onset favors malignancy, as most patients with malignancy and hypercalcemia are dead within 6 months of onset of hypercalcemia; 35 years of hypercalcemia would suggest rather benign disease of early onset, make one think of genetic syndromes: familial hypocalciuric hypercalcemia if urine calcium is low or mild FMEN1 if urine calcium is elevated.

7. Acutely, attempt to increase hydration and volume status to increase filtration and clearance of Ca2+ in the kidneys. Furosemide may be required for continued calciuresis. Medical therapy of primary hyperparathyroidism is not well defined, but may include oral phosphates, or estrogens and/or progestins in post menopausal women. Intravenous bisphosphonates, and even oral bisphosphonates, may be useful for short-term or long-term management of hypercalcemia, respectively. Definitive therapy involves surgical removal of abnormal parathyroid tissue. Glucocorticoids can be employed in vitamin D related hypercalcemia. Calcitonin, intravenous bisphosphonates, plicamycin (old name Mithramycin), and gallium nitrate, work to decrease osteoclast activity and can also be useful in the treatment of hypercalcemia. Newer agent such as calcimimetics (sensipar) have a role in the long term management of hyperparathyroidism in those that are not surgical candidates.

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Small Group

C.D. is a middle-aged appearing man with a 10 year history of progressive weakness, weight loss, and low back and pelvic pain. He has noted a weight loss of 50 lbs over the last few years that has not abated despite an unsatiable appetite for an unusual liquid diet. He admits to taking antacids for recurrent abdominal discomfort, and has bouts of intermittent diarrhea. He avoids dairy products because they cause "bloating" and aggravate his diarrhea. His past medical history is significant for a fractured proximal femur sustained five years earlier after experiencing a "rough landing" due to sudden onset of a painful "charley horse" cramp in his legs. He has difficulty with night vision. During a recent hospitalization a diagnosis of adult celiac disease was made. Routine bone x rays showed a generalized decrease in bone density. He develops severe muscle cramps in his hand when you take his blood pressure.

Social History: He does not smoke: he states, "I don't drink wine." He works at night in a blood bank and sleeps during the day; he tries to avoid sunlight. Was married before emigrating to this country from central Europe, but now dates rarely.

Review of systems: Irrational fears of running water and religious symbols.

Physical exam: BP 105/70, pulse 88; weight 92 lbs.
General: Chronically ill appearing, pale, white male;
Teeth: Excellent dentition
Skin: several ecchymoses
Eyes: conjunctiva very pale
Mouth: Glossitis
Lungs: Clear
Cor: 2/6 flow murmur
Abd: benign
Ext: generalized muscle weakness and decreased muscle mass; slightly diminished vibration and proprioception in the lower extremities
Neuro: non-focal

Lab: Hgb: 6.0 MCV: 102
WBC: 5,000 [with hypersegmented polys]
Protime 14, seconds (normal 12)

Electrolytes are normal
Calcium 6.5, Phosphorus 2.0; serum albumin 3.0 mg/dl (nl 3.5-5.0)
Creatinine 1.0 mg/dl and BUN 10 mg/dl

Urinary calcium 50 mg/day,
Tubular reabsorption of phosphorous 68%
Fecal Fat: 20 g/d on 100 gram fat diet
(nl < 5 grams/day)


Questions:

1. What is basis for this patient's generalized debility?
2. Why does this patient have hypocalcemia? Hypophosphatemia? What is the significance of the low albumen level?
3. What are the primary sources of vitamin D? What is the significance of the avoidance of sunlight? Which lab tests can help assess a patient's vitamin D stores?
4. What is the most active form of vitamin D, and what metabolic steps are required for its formation?
5. What would you expect the serum concentration of 25-hydroxy vitamin D to be? Why?
6. What are the symptoms and signs of hypocalcemia? Does this patient have any?
7. What do you expect the serum level of iPTH to be? Why?
8. What are major actions of vitamin D on the intestine and bone?

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Answers:

1. This patient has non tropical sprue or adult celiac disease. He has multiple manifestations of malabsorption including:

a. weight loss, loss of muscle mass, hypoalbuminemia
b. macrocytic anemia (B12 deficiency), glossitis, neuro sensory defects
c. loss of fat soluble vitamins:
K prolonged protime
D osteomalacia
A - poor night vision

Vitamin D deficiency rarely occurs in subjects with malabsorption or gastrectomy syndromes unless they have very little uv light exposure and thereby have a primary dependency on dietary intake of vitamin D.

2. Hypocalcemia: Decreased gastrointestinal absorption of calcium due to reduced vitamin D [specifically decreased 1,25(OH),2D] and possible damage to intestinal absorptive surface. Hypophosphatemia: Decreased intestinal absorption as above, and increased renal clearance because of secondary hyperparathyroidism. Low albumin: indicates poor nutritional status; also important as 50% of total serum calcium circulates bound to albumin, so reduced albumin levels can lead to reduced total calcium levels; ionized calcium concentration, which is the physiologically active form of calcium, may be normal. Although algorithms have been proposed that "compensate" for low albumin levels and yield a "corrected" calcium value (e.g., add 0.8 mg/dl to calcium concentration for each 1 mg/dl decrease in serum albumin from 4.0 mg/dl), none is as accurate as measuring the ionized calcium level directly.

3. Vitamin D arises from:

a. skin: cholecalciferol (D3) is derived from conversion of 7 dehydrocholesterol by UV light in the skin
b. diet: intake of cholecalciferol (animal sources, D3) and ergocalciferol (plant, D2); milk and other foods are fortified with vitamin D.

Levels of 25-hydroxy vitamin D are usually a good measure of sunlight exposure (25(0H) D3) and dietary Vitamin D intake (25(0H)D2)

4. 1,25(0H)2 Vit D is the most active metabolite. Its formation requires the substrate-dependent 25 hydroxylation of cholecalciferol and ergocalciferol by the liver, and the tightly regulated 1α hydroxylation of 25(OH)D by the kidney. The latter reaction is tightly controlled: rate of formation of 1,25(0H),D is increased by low phosphorous and elevated PTH, and decreased by elevated phosphorous (or calcium) and decreased PTH.

5. The patient has multiple reasons for low Vit D levels:

a. Steatorrhea is associated with decreased absorption of fats and fat-soluble vitamins, such as vitamin D. Normally, dietary Vit D is absorbed in the duodenum and jejunum, and enters the lymphatic channels. Loss of bile salts and fat malabsorption impairs intestinal transport of vitamin D.

b. Nutrition: for example strict vegetarians may be prone to diminished Vit D intake.
c. Avoidance of sunlight.
d. Low levels of serum D binding protein (DBP) due to nutritional deficiency and intestinal loss of plasma DBP.

6. The patient's hypocalcemia (decreased ionized calcium) occurs on the basis of Vitamin D deficiency; however, it also reflects diminished total calcium levels on the basis of hypoalbuminemia. The physiological effects of calcium are mediated via the level of ionized calcium. Low albumin levels may result in low total calcium levels; the ionized calcium may, however, be normal. This patient's total calcium is still low after mathematical correction for albumin levels, which implies a decreased ionized calcium.

Symptoms of hypocalcemia include: paresthesias, tetany, seizures, personality changes; symptoms associated with osteomalacia (bone pain, fractures, muscle weakness in adults). Chvostek's and Trousseau's signs (muscle cramping in hand when blood pressure is taken) may be present.


7. In chronic Vit D deficiency, PTH levels may be elevated secondary to hypocalcemia Malabsorption of magnesium may result in diminished PTH secretion and/or decreased action of PTH on tissues.

8. Vitamin D stimulates calcium and phosphorous transport from the intestinal lumen. On the bone, it appears to stimulate osteocytic osteolysis and potentiate the effects of PI H on bone resorption. Secondary hyperparathyroidism in the absence of adequate 1,~5(0H),D is generally not adequate to maintain normal serum calcium levels.

9. Vitamin D deficiency results in an impairment of bone mineralization. Its manifestations depend on the duration, severity, and age of the patient. In children, defective bone mineralization produces epiphyseal dysplasia, retardation of growth, and other skeletal abnormalities - it is called rickets.

In adults, generalized loss of bone density results in pathologic fractures, bone proximal muscle weakness, and osteomalacia due to impaired mineralization of osteoid.

Radiographic features include pseudofractures (Milkman's or Looser's lines), loss of trabeculae, thinning of cortices in long bones. In children, radiographic changes include: widening of the growth plates, cupping and widening of metaphyses, gross deformities (kyphoscoliosis, bowing of extremities. Histology of osteomalacic bone reveals a mineralization defect: there is abundant non calcified bone matrix protein (osteoid), and delayed or aberrant deposition of calcium phosphorous (hydroxyapatite).

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Hypocalcemia

DiGeorge Syndrome?

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CATCH-22

Cardiac
Abnormal facies
Thymic aplasia
Cleft palate
Hypocalcemia

22q deletion