Normal Anatomy

• Embryology

1.     Upper parathyroids derived from brachial pouch 4; found on posterior Superior aspect of the thyroid.

2.     lower derived from B.P. 3; can be found from inferior pole of the thyroid to the thymus.  May be intrathyroidal or intrathymic

• Gross Anatomy

1.     in infancy – composed mainly of sheets of chief cells

2.     at 25- maximal amount of fat present (30%)

• Histology

1)     Chief cells: major source of parathyroid hormone

2)     Oxyphil cells – larger than chief cells with increased pink cytoplasm; lots of mito

3)     Transitional cells

4)     Clear cells – chief cells filled with lipid, glycogen, and lysosomes.  These are inactive chief cells

Biochemistry

• Parathyroid Hormone

Ø  Function: maintenance of extracellular Ca²⁺ (ionized)

Ø  Ca²⁺ and Mg²⁺ sensitive – in plasma

Ø  Gene locus for PTH – chromosome 11

Ø  Structure:

1)     pre-pro-parathyroid hormone cleaved in the chief cell

2)     pro-parathyroid hormone cleaved in plasma to produce PTH

3)     Two subunits:

a.     N terminal – active

b.     C terminal – no activity

Ø  Mechanism of action

1)     binds to membrane PTH receptor complex

2)     activation of adenylate cyclase Þ increased intracellular cAMP which leads to

a.     increased Ca absorption from the GI tract (Vit D is synthesized in the kidney in response to PTH)

b.     increased renal tubular resorption of Ca²⁺

c.      increased phosphate excretion

d.     mobilized Ca from bone (requires Vit D, 1,25)

Ø  REMEMER

PTH – ^Ca²⁺ and ^vPO₄^3- levels in plasma

Calcitonin – ^v Ca²⁺ and ^vPO₄^3- levels in plasma

• Calcium

Ø  99% is in bone, 1% in extracellular fluid (what about the intracellular?)

Ø  acidosis leads to an increase in ionized Ca²⁺

Ø  alkalosis causes a decrease in ionized Ca

Ø  Protein concentrations in the plasma affect the measures amounts of total Ca because Ca is reversibly bound to plasma proteins (albumin and globulins).  Must adjust for hyper- or hypo-proteinuria

• Inorganic Phosphorus

Ø  present in body as phosphate in even distribution between extra- and intra- cellular stores

Ø  normal elevations in serum levels in children and young adults

• Vitamin D and Metabolites

Ø  Vit D₃ produced in skin by action of sunlight; Vit D₂ produced in plants (used as a food additive)

Ø  Both undergo hydroxylation in the kidney to the most active metabolite 1,25-(OH)₂-Vit D₃.

Pathology

Hyperparathyroidism

• Primary Hyperparathyroidism

Ø  intrinsic disorder of the parathyroids

Ø  results in ^ Ca and ^vPO₄

Ø  Remember: due to hyperthyroidism or malignancy

Ø  Clinical presentation

1)     often asymptomatic

2)     GI: nausea, vomiting, peptic ulcers, pancreatitis

3)     Renal: recurrent nephrolithiasis and nephrocalcinosis (due to inc Ca in urine)

4)     Skeletal: loss of mineralized bone with osteoporosis

5)     HTN

6)     Muscular weakness

Ø  Lab findings

1)     increased PTH

2)     increased serum and urinary Ca

3)     decreased plasma PO₄

Ø  Causes

• 80% single adenoma, 2-3% double adenoma, 2-3% parathyroid CA, 15% parathyroid hyperplasia, MEN I and IIa

• Parathyroid Adenomas

Ø  peak incidence in middle age

Ø  must visualize all four glands at the time of surgery!  Remember ectopic sites.

Ø  Inferior gland involvement most common

Ø  MICRO

1)     well encapsulated, most are comprised of chief cells (can have others)

2)     oxyphil cell adenomas are usually non-functional

3)     mitoses are rare

4)     The presence of a rim of normal or atrophic parathyroid tissue with scattered fat cells external to capsule – differentiates adenoma from hyperplasia

• Parathyroid Carcinoma

Ø  rare cause of hyperparathyroidism

Ø  usu – functional tumor involving just one gland

Ø  enclosed by a dense fibrous (lats larger than adenoma) capsule

Ø  may be adherent to surrounding structures

Ø  Diagnosis of malignancy – requires metastasis &/or local invasion

Ø  MICRO

1)     trabecular growth pattern

2)     mitoses present

3)     CAPSULAR INVASION

4)     BLOOD VESSEL INVASION

Ø  Prognosis: death is usually the result of the complications of the hyperparathyroidism

• Primary Hyperplasia

Ø  diffuse enlargement of all 4 glands is possible

Ø  can occur as part of MEN I and IIa

Ø  15% of all primary hyperparathyroidism

Ø  MICRO

1)     hyperplasia can be diffuse or nodular

2)     usually composed of chief cells

Ø  Chief Cell Hyperplasia

1)     hyperplasia is not uniform throughout the gland

2)     variability in number of glands involved

3)     MICRO

• solid areas of chief cells with few fat cells

Ø  Clear Cell Hyperplasia

1)     glands larger that Chief cell hyperplasia

2)     uniform distribution

3)     usually affects all four glands

• Secondary Hyperparathyroidism

Ø  most often in patient with chronic renal failure

Ø  also seen in Vit D deficiency or osteomalacia

Ø  due to hypersecretion of PTH in response to decrease blood Ca levels (end organ resistance to the PTH)

Ø  MICRO

• same as 1^o hypreparathyroidism
• diffuse or nodular chief cell hyperplasia

Ø  Lab findings

1)     decreased serum Ca

2)     increased PTH

Hypoparathyroidism

• defined: inadequate secretion of PTH or hormone is ineffective
• results in: decreased action of PTH on kidney, bone
• leads to : ^v Ca and ^ PO₄ in plasma
• Clinical Presentation

1)     when mild clinically undetectable

9 C’s of Hypocalcemia:

cramps

convulsions

cataracts

CSF pressure increase (pseudotumor cerebri, papilledema)

Calcification of the basal ganglia

Craziness

Chvostek’s sign

Carpopedal spasms (Trousseau’s sign)

Cardiogram changes – QT prolongation (abnormalities of cardiac conduction)

• Lab findings

1)     decreased serum Ca

2)     decreased to undetectable levels of PTH in plasma

• Causes

1)     most common is iatrogenic – ex. Surgery to the head or neck

2)     idiopathic – rare

3)     Familial hyperparathyroidism – part of the autoimmune polyglandular syndromes

4)     DiGeorge’s syndrome – thymic and parathyroid hypoplasia (brachial pouches form incorrectly)

5)     Radiotherapy, metastases, iron storage disease, Wilson’s disease

Pseudohypoparathyroidism

• abnormality in the PTH receptor complex found on cell membranes
• leads to a lack of responsiveness to PTH
• ^v serum Ca and ^ serum PTH (maybe a lot)
• Clinical: Albright’s hereditary osteodystrophy)

Pseudopseudohypoparathyroidism (that’s right 2 pseudos)

• clinical picture identical to pseudohypoparathyroidism except: normal Ca, and PO₄ and normal response to PTH
• I don’t really understand why there is such a disease? Wouldn’t you be normal then?

Multiple Endocrine Neoplasia

MEN type I – Wermer syndrome

MEN type IIa – Sipple Syndrome

MEN type IIb – Previously MEN III

Type                           Tumors involved       Chromosome#   KEY to REM

MEN Type I                  Pituitary Adenoma                     11q           Three P’s

(Wermer syndrome)      Parathyroid hyperplasia/

adenoma

Pancreatic islet cell tumor

MEN Type IIa               Adrenal Pheochromocytoma         10          ATP

(Sipple Syndrome)        Thyroid Medullary Carcinoma

Parathyroid hyperplasia

MEN Type IIb               Adrenal pheochromocytoma                      ATM

Thyroid Medullary Carcinoma

Mucosal Neuroma Syndrome

Tags: adenylate cyclase, Calcium, DiGeorge's syndrome, Familial hyperparathyroidism, hydroxylation, Hyperparathyroidism, Hyperplasia, Inorganic Phosphorus, Metabolites, oxyphil cell adenomas, Oxyphil cells, Parathyroid Adenomas, Parathyroid Carcinoma, Parathyroid Hormone, Pseudohypoparathyroidism, Pseudopseudohypoparathyroidism, thymus, thyroid, Trousseau's sign, Wilson's disease

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