Endocrine Pathology: Parathyroid gland

Question 1

What are the types of cells found “dispersed” in aggreggates throughout the body?

Answer 1

C cells of the thyroid

GI NE system

Carotid body

Merkel cells of the skin

Pulmonary neuroendocrine cells

Question 2

What are the types of islet cell growth disorders?

Answer 2

Hyperplasia

Tumours: Pancreatic neuroendocrine tumours.

Question 3

How common are islet cell growth disorders?

Answer 3

All are rare (2% of pancreatic tumours)

Question 4

What are the features of islet cell growth disorders?

Answer 4

Usually small (<2cm)

Some are MEN syndrome-associated

May be functional, non-functional, or asymptomatic

Solitary or multiple

Benign or malignant

Question 5

What are the functional syndromes that arise from islet cell growth disorders?

Answer 5

Hyperinsulinism (“insulinoma”): usually benign/grade 1 (90%), episodic hypoglycaemia which may be precipitated by exercise or fasting and relieved by glucose.

Zollinger Ellison syndrome: Excess gastrin secretion from gastrinoma of pancreas/duodenum/peripancreatic tissue: this results in severe intractable peptic ulceration with or without diarrhoea. 25% associated with MEN1 syndrome

Others - VIPoma, Glucagonoma, Somatostatinoma.(half of these are malignant and cause diarrhoea + other symptoms depending on secretory product)

Question 6

What is the prognosis like in Zollinger Ellison syndrome?

Answer 6

~50% are malignant gastrinomas.

~25% associated with MEN1 syndrome.

Question 7

What are the NE pathologies that can arise in NE cells?

Answer 7

Hyperplasia (usually incidental findings, can be precursor to malignancy)

Neoplasia (benign or malignant)

Terminology is not consistent between organs/systems and has been revised multiple times.

Question 8

How are neoplasms named in NE cells?

Answer 8

Terminology is not consistent between organs/systems because behaviour is not the same in different locations. In some sites low grade tumours are more common and others high grade tumours are more common.

Question 9

What are the features of NE tumours?

Answer 9

They are usually incidentally found and may produce hormones or hormone like peptides.

Question 10

How is hypercalcaemia related to parathyroid pathology?

Answer 10

Parathyroid pathology is essentially about calcium, hypercacaemia in particular.

Hypercalcaemia can be both a cause or an effect of parathyroid disease but it is not the only cause of hypercalcaemia.

Question 11

What does calcitonin do? Where is it produced?

Answer 11

Produced in the thyroid gland (by C cells) and stimulates calcium deposition in bones and reduces calcium uptake in kidneys.

Question 12

What does parathyroid hormone do? Where is it produced?

Answer 12

Produced in the parathyroid glands (chief cells) and Increases calcium in the blood by increasing calcium release from bones and calcium uptake from kidneys.

Question 13

What are the variants of chief cells in the parathyroid gland?

Answer 13

Oxyphil and water clear

Question 14

What does PTH do?

Answer 14

Bone resorption

Renal tubular resorption of calcium

Increases conversion of vitD to active form in kidney

with vitamin D promotes calcium absorption from small intestine

Increases urinary phosphate excretion causing phosphaturia

Net effect is to increase serum calcium

Question 15

What kind of tissue are chief cells mixed with?

Answer 15

Fat (up to 30%)

Question 16

How can Parathyroid Gland pathology lead to hypocalcaemia?

Answer 16

Acutely due to accidental damage/removal of parathyroids during thyroid surgery.

Chronic cause is usually caused by chronic renal failure, vitD deficiency, or intestinal malabsorption of calcium

Question 17

What are the symptoms of hypocalcaemia?

Answer 17

Results in neuromuscular irritibility (calcium channels block sodium channels and lower calcium lowers depolarisation threshold)

CATs go numb (Convulsions, arrhythmias, Tetany, and numbness/parasthesia

CNS: fatigue, depression, altered cognition

Question 18

What causes hypercalcaemia?

Answer 18

Entry of calcium into the circulation exceeds the excretion of calcium into the urine or deposition in bone.

Most common causes are:

Hyperparathyroidism (primary due to adenoma or malignancy)

Hypercalcaemia of malignancy (Bone osteolysis due to metastases in the skeleton) + Metabolic effects of malignant tumours (PTHrP secretion from tumours)

Many other less common reasons (Drugs, metabolic/genetic disorders, chronic granulomatous disease)

Question 19

What are the parathyroid mediated causes of hypercalcaemia?

Answer 19

Primary hyperparathyroidism (sporadic)

Familial hypocalciuric hypercalcaemia

Tertiary hyperparathyroidism (renal failure)

Question 20

What are the non-parathyroid mediated causes of hypercalcaemia?

Answer 20

Hypercalcaemia of malignancy (PTHrp, activation of extrarenal 1 alpha-hydroxylase (increased calcitriol), osteolytic bone metastases and local cytokines.

Vitamin D intoxication

Chronic granulomatous disorders (Wegener’s and sarcoidosis) due to activation of 1 alpha-hydroxylase (increased calcitriol)

Question 21

How does renal failure lead to PTH mediated hypercalcaemia?

Answer 21

Renal failure results in retention of phosphate inappropriately (disrupts Ca/PO4 homeostasis) which activates feedback loop leading to PTH secretion.

Question 22

How does excess vitD result in hypercalcaemia?

Answer 22

Excess vitD results in increased absorption, resorption, and mobilisation of calcium resulting in hypercalcaemia.

Question 23

What conditions most commonly cause hypercalcaemia?

Answer 23

Excessive PTH

Disrupted Ca/PO4 homeostasis (due to renal failure)

Question 24

What are the clinical manifestations of hypercalcaemia?

Answer 24

Stones, Bones,Groans, and Moans. (+CVS, Ocular, Dermatological)

Renal stones: Nephrolithiasis, dehydration, polyuria/polydipsia

Skeleton “bones”: Bone pain

GI “Abdominal moans”: Nausea, vomiting, anorexia, weight loss, constipation, abdominal pain

Neuromuscular “psychic groans”: Lethargy and fatigue, muscle weakness

Cardiovascular: Vascular calcification

Question 25

Important note about hypercalcaemia:

Answer 25

Hypercalcaemia can be a tricky clinical problem with subtle or extreme manifestations and requires a thorough diagnostic approach.

Presentation in clinic may be weakness, tiredness, vague abdominal pain, and aching joints. Hyperparathyroidism is a major cause but not the only one.

Question 26

How is hyperparathyroidism classified?

Answer 26

Primary HP: Excess PTH production (Parathyroid)

Secondary HP: Other disease causes PTH (abnormal homeostasis)

Tertiary HP: Autonomous PTH secretion, caused by long standing secondary HP

Ectopic secretion: PTrP (paraneoplastic from other malignancies and is feedback independent)

Question 27

What are the signs and symptoms of parathyroid gland pathology?

Answer 27

Usually hyperparathyroidism (PT adenoma or PT hyperplasia)

Malignancy is rare

Hypoparathyroidism is rare (usually genetic in origin and results in hypocalcaemia)

Mass effect is not really an issue in this site.

Parathyroids may be in unusal sites (intrathyroid, mediastinal, intrathymic)

Question 28

What is a parathyroid adenoma?

Answer 28

Benign neoplasm of the parathyroid epithelium which accounts for 90% of hyperparathyroidism observed.

Usually solitary but if multiple it could be due to MEN1 mutation.

Question 29

How does parathyroid adenoma look like on histology?

Answer 29

Sheets, acini, follicles, trabeculae.

Uniformity of cell type

Loss of reticulin network

No intraglandular fat

Rim of normal

Question 30

What are the features of parathyroid hyperplasia?

Answer 30

Increased number of cells in all glands (may be asymmetrical)

Total weight is usually <1 gram (as opposed to adenomas that reach 5 grams)

Usually mainly chief cells but may have mixed cell type or a nodular pattern.

Usually sporadic but can be familial: MEN1, homozygous loss of suppressor gene on chromosome 11, less commonly MEN 2a.

Question 31

What are multiple endocrine neoplasia syndromes?

Answer 31

A group of uncommon inherited diseases characterised by:

Proliferative lesions (Hyperplasia, adenomas, and carcinomas) of multiple endocrine organs.

One gland or multiple glands (can be multifocal)

Tumours occur at a younger age than sporadic tumours

Malignancies are usually more aggressive and recur in a higher proportion of cases than sporadic tumours

Question 32

How are multiple endocrine neoplasia syndromes inherited?

Answer 32

Autosomal dominant - family follow-up is important and early prophylactic treatment is necessary.

Question 33

What are the MEN syndromes?

Answer 33

MEN-1 (Wermer syndrome) is caused by loss of tumour suppressor gene 11q13

MEN-2 (RET proto-oncogene mutations)

Question 34

What are the symptoms of MEN-1 syndrome?

Answer 34

3 Ps:

Parathyroid hyperplasia/adenoma

Pancreatic neuroendocrine tumours of endocrine pancreas

Pituitary prolactinomas and less commonly acromegaly

In addition to the 3 Ps there are also adrenocortical adenomas that occur as well as carcinoid tumours of dispersed neuroendocrine system.

Question 35

How common is MEN-1 syndrome?

Answer 35

2/100k

Question 36

What are the types of MEN-2?

Answer 36

3 types all have medullary thyroid carcinoma as main manifestation.

MEN-2A (Sipple syndrome): MTC plus adrenal phaechromocytoma

MEN-2B: MTC plus adrenal phaeochromocytoma

Familial MTC: No other organs affected

Question 37

What tests might be useful to test for parathyroid pathology?

Answer 37

Calcium levels (Mg/PO4)

Renal function

Hormonal assay

Frozen section

Histopathology (Excision of involved glands, definitive assessment of diagnosis, invasion, no role for FNA or partial biopsy)