Hyperparathyroidism

Question 1

Types of cells in the parathyroid gland, their histology, and common location of ectopic parathyroid tissue

Answer 1

Cheif Cells - secrete PTH. Small round nucleus, mostly clear cytoplas

Oxyphil cells - unclear major function, can secrete PTH-rp, and calcitriol, are more eiosinophilic.

Ectopic mediastinal parathyroid tissue in 1-5% of people, often in the thymus.

Question 2

Where is PTH secreted, and where is does it get converted to active form?

Answer 2

• Synthesized in chief cells as large precursor – pre-proparathyroid hormone
• Cleaved intracellularly into proparathyroid hormone then to final 84 AA PTH
• PTH then metabolized by liver into hormonally active N-term and inactive C-term

Question 3

What are the causes of hypercalcemia?

Answer 3

90% of cases:

• Primary hyperparathyroidism
  
  • secretory adenoma of parathyroid
  • secretory carcinoma of the breast or lung
• Renal insufficiency, causing low vitamin D, and secondary hyperparathyroidism.

Other causes

• Hyperthyroidism
• Paget disease
• Immobilization
• Vitamin D toxicity
• Vitamin A toxicity
• Tertiary hyperparathyroidism after prolonged secondary from renal insuff.
• Granulomatous disease of parathyroid
• Milk Alkali syndrome
• Rhabdomyolysis and acute renal failure
• Benign familial hypocalciuric hypercalcemia
  
  • Renal hypersensitivity of the CaSR.
• Adrenal insufficiency

Question 4

Frequencies of the different causes of primary hyperparathyroidism

Answer 4

Adenoma • 85-95% ~3% multiple adenoma

Hyperplasia • 5-10% can be diffuse or nodular

Adenocarcinoma • 1%

Question 5

Clinical presentation of parathyroid secretory adenoma

Answer 5

4:1 female preference

Most often results in asymptomatic hypercalcemia; however, may present with consequences of increased PTH and hypercalcemia such as

“painful bones, renal stones, abdominal groans, and
psychic moans.”

• Nephrolithiasis (calcium oxalate stones)
• Nephrocaleinosis—metastatic calcification of renal tubules (Pig.15.9), potentially leading to renal insufficiency and polyuria
• CNS disturbances (e.g., depression and seizures)
• Constipation peptic ulcer disease
• acute pancreatitis (uncommon but possible)
• Osteitis fibrosa cystica—resorption of bone leading to fibrosis and cystic spaces
• Periosteal bone resorption.

Laboratory findings

• T serum PTH, T serum calcium, I serum phosphate, T urinary cAMP, and T serum alkaline phosphatase.

Question 6

MEN-1, MEN-2, MEN-3 syndromes

Basic, shared characteristics

Answer 6

Tumors occur at a younger age than that typical for sporadic cancers.

They arise in multiple endocrine organs, either synchronously or metachronously.

Even in one organ, the tumors often are multifocal.

The tumors usually are preceded by an asymptomatic stage of endocrine hyperplasia involving the cell of origin of the tumor (for example, patients with MEN-2 almost universally demonstrate C cell hyperplasia in the thyroid parenchyma adjacent to medullary thyroid carcinomas).

These tumors are usually more aggressive and recur in a
higher proportion of cases than similar endocrine tumors
that occur sporadically.

Question 7

MEN-1 gene locus and function

Answer 7

11q13, a tumor suppressor.

Question 8

MEN-1 affected organs

Answer 8

3 p’s

parathyroid, pancreas, and pituitary

Parathyroid: primary hyperparathyroidism, is most common MEN-1 symptom. Causes both hyperplasia and adenoma.

Pancreas: Pancreatic malignant tumors are the main cause of death. Zollinger-ellison syndrome from gastinomas and insulinomas.

Pituitary: Prolactinoma macroadenomas mainly, sometimes GH-adenomas and acromegaly.

Question 9

MEN-2

Answer 9

Both caused by mutations to the 10q11.2 locus

All patients with detected mutations are advised to have prophylactic thyroidectomy to prevent medullary thyroid carcinoma.

MEN-2A:

• autosomal dominant inheritance
• RET kinase activating mutations
• Parathyroid
• Thyroid - medullary carcinoma
• Adrenal medulla

MEN-2B

• specific single amino acid change to the RET protein.
• NO parathyroid involement.
• Thyroid - medullary carcinoma
• Adrenal medulla
• Extraendocrine manifestations
  
  • Ganglioneuromas of the mucosa, GI, lips, and tongue
• Marfanoid habitus, very long axial bones resembling marfan synd.

Question 10

Symptoms of hyperPTHism

Answer 10

1. Most patients are asymptomatic or with minimal symptoms.
2. Disease may run a benign course for years prior detection.
3. Osteitis fibrosa cystica - cystic lesions in the bone, bone pain, also called brown tumors?
4. Brown tumors of humerus
   
   • ​​fibrous tissue tumor-like lesion of the bone due to excessive osteoclast activity. hemosiderin deposits give it a brown color.
5. Subperiosteal bone resorption is the most consistent and specific finding of hyperparathyroidism and is virtually pathognomonic of the condition..
6. Symptoms of hypercalcaemia
   
   • ​​​​Think of hypercalcemia if patient:
     
     • ​is confused, unconscious
     • osteoperosis
     • recurrent kidnery stones
     • recurrent pancreatitis
     • short QT

• Central nervous system
  
  • Impaired mental function,
  • loss of memory,
  • depression,
  • somnolence,
  • coma
• Neuromuscular Weakness,
• arthralgias,
• severe pruritus (metast. calcification of skin),
• Kertopathy, cloudy cornea from calcium deposition.
• restless leg sy (no comfortable position)
• Cardiovascular Hypertension,
• bradycardia,
• shortening of QT
• Renal Polyuria,
• nephrocalcinosis,
• recurrent Ca nephrolithiasis
• Gastrointestinal Anorexia,
• vomiting,
• constipation,
• peptic ulcer,
• pancreatitis
• Rheumatologic Gout,
• pseudogout (intraarticular Ca-pyrophosphate crystals),
• chondrocalcinosis

Question 11

Tests/diagnosis for hyperparathyroidism

Answer 11

• Hypercalcemia
• Hypophosphatemia
• PTH level increased
• Calcitriol level increased
• Bone radiography, periosteal resorption and osteitis cystica, brown tumors.
• Sestamibi Technetium Scanning- is uptaken by parathyroid and myocardium. taken up faster by hyperfunctional parathyroid adenomas.
• Ultrasound, CT, MRI.

Question 12

Treatment

Answer 12

Surgery:

indicated if there are overt clinical symptoms, age under 50 years, hypercalcemia, excessive urinary excretion, declining bone mineral density, significant co-morbidities, patients request.

Observation

• No hypercalcemia
• No kidney stone
• No bone disease
• No mental defects
• Limit Calcium intake
• Maintain hydration and phosphate intake
• Follow the patient.

Question 13

Treatments for hypercalcemia

Answer 13

Fluid intake increase-3-4 L phys. NaCl infusion/day+ Furosemide 80-160mg/die SeMg! K!, saline infusions, plus diuretic, selectively drop calcium

Steroid - 40-100mg prednisolon/die (best in certain lymphomas, and granulomatous diseases)

Inhibition of bone resorption and osteoclast activity - Calcitonin sc or im. 4-8 IU/kg 4x/die for 2 days ,- Bisphosphonates( for malignancy): pamidronate 30mg infusion/die for 3 days or zoledronate 4mg effective for- 4-6 weeks(kidney!)

Gallium nitrate (inhibition of PTHsecretion and osteoclast activity) effective in 70% of malignant cases for 10-14 days

Cinacalcet (calcimimetic drug, affects on Ca-senzing receptor) p.os 30-180mg/die for inoperable parathyroid diseases

Question 14

What is are the classifications for pathologic calcifications?

Answer 14

Dystrophy calcification:

• occurs in dead tissues, not related to derangements in calcium metabolism/homeostasis
• is encountered in areas of necrosis of any type
• It is virtually inevitable in the atheromas of advanced atherosclerosis
• Dystrophic calcification of the aortic valves is an important cause of aortic stenosis in elderly persons
• Seen in caseous necrosis granulomas.
• Involves initiation on a nucleation site which is occurs in membrane bound
  vesicles about 200 nm in diameter; in normal cartilage and bone they are known as matrix vesicles, and in pathologic calcification they derive from degenerating
  cells.
• Intracellular calcification occurs in the mitochondria of dead or dying cells that have lost their ability to regulate intracellular calcium. After initiation in either location, propagation of crystal formation occurs. This is dependent on the concentration of Ca2+ and PO4−, the presence of mineral inhibitors, and the degree of collagenization, which enhances the rate of crystal growth.

Metastatic calcification: occurs in otherwise normal tissues, secondary to hypercalcemia or other pathology.

1. Hyperparathyroidism
   
   1. Primary
   2. ectopic PTH-rp
2. Bone destruction
   
   • Paget
   • Lytic bone lesions from tumors
     
     • Prostate metastasis
     • Breast metastasis
     • Lung metastasis
     • Mult. myeloma
     • Leukemia
3. Vitamin D disorders
   
   • Intoxication
   • Sarcoidosis - excessive macrophage activation of vitamin D
4. Renal failure, renal osteodystrophy.

gross examination of any type of calcification is seen as fine white granules or clumps, felt as gritty deposits.

Question 15

Histology and gross morphology of parathyroid adenomas

Answer 15

By definition it is confined to a single gland.

Well circumscribed, soft, brown/tan nodule, with a thin capsule. Usually between 0.5 and 5g.

Compresses the remaining gland and it is usually shrunken/atrophic due to inhibition by the chronic hypercalcemia.

They are composed of cheif cells, with some nests of oxyphil cells, and lack the adipose of normal gland.

The cheif cells can look relatively normal, but have more nuclear variability, and often present with bizarre pelomorphic nuclei that does not indicate malignancy. This is seen in some endocrine tumors and is called endocrine atypia - especially in parathyroids and adrenal gland tumors. But mitotic figures are still low/not present.

Question 16

Histology and morphology of parathyroid hyperplasia

Answer 16

Typically in multiple pth glands, with the glands just being enlarged still the total weight of the glands is less than 1g.

Histologically:

Cheif cell hyperplasia usually, with little adipose

or, less commonly, the cheif cells acculmulate lots of glycogen, and it is called water-clear cell hyperplasia_._

Question 17

Morphology and histology of parathyroid carcinoma

Answer 17

highly variable presentation

Gross morphology:

Can be very similar to adenomas with a distinct capsule, or clearly invasive and malignant.

Are in a single gland.

Histology:

Uniform cells that resemble normal parathyroid cells, and determination based on cytology is not reliable. It is defined based on invasion of surrounding tissue (thyroid gland) and metastasis.

Thus, any PTH adenoma should be removed.

Question 18

What are the genetic mutations associated with parathyroid neoplasia?

Answer 18

Cyclin D1 overexpression is in 40% of adenomas

Specifically a Cyclin D1 inversion of chromosome 11 is in 10-20%, placing the Cyclin D1 gene next to the gene for PTH itself. Causing increased Cyclin D1 expression.