MEN 1 Endocri JB

Question 1

How much calcium would you consume from the 1000g intake

Answer 1

300mg, of which, 125mg will be excreted.
in the body, there are pools of up to 900mg of calcium in ECF, 1000mg in bone.
Absorption through GIT is mediated via active vitamin D

Question 2

how does PTH mediate calcium homeostasis?

Answer 2

PTH action includes:
RENAL
- calcium reabsorption from distal tubule
- Inhibition of proximal tubule phosphate reabsorption
- Proximal tubule synthesis of 1,25 Vitamin D3
SKELETAL
- PTH stimulates osteoclastic bone resorption GIT
- 1,25 Vitamin D stimulates small intestinal receptors, increasing the absorption of calcium

Question 3

Explain CALCIUM HOMEOSTASIS

Answer 3

alterations in extracellular calcium result in short and long term changes in PTH.

• ther eis an inverse sigmoid relationship between PTH secretion and extracellular calcium.
• Extracellular calcium concentration producing 50% maximal PTH provides a ‘set point’ for calcium.
• Elevations in set point seen in primary hyperparathyroidism and FHH

Question 4

What are the clinical manifestaitions of hypercalcemia

Answer 4

Non specific: anorexia, abdo pain, constipation, lethargy, headache, altered mentation, depression.
Organ specific:
- Gastrointestinal: constipation, pancreatitis
- Renal: calculus, RTA, chronic hypercalcaemic nephropathy
- Neuropsychiatric and neuromuscular:
- CVS: hypertension

Question 5

how do we classify hyperparathyroidism?

Answer 5

Classification is based on the level of PARATHYROID HORMONE PTH

• PTH dependent: primary hyperparathyroidism - > most PHPT associated with callcium <3.0mmol
• PTH independent (malignancy, Vit D excess)

Question 6

How do we assess hyperparathyroidism?

Answer 6

Measure PTH paired with calcium
- If PTH non suppressed = primary hyperparathyroidism
: MUST exclude FAMILIAL HYPOCALCIURIC HYPERCALCEMIA.

• If PTH is suppressed then it is non-parathyroid mediated:
• neoplasia (PTHrp, osteolytic mets)
• Vitamin D excess (exogenous, granulomatous)
• Thyroxtoxicosis, adrenal insufficiency
• Thiazide diuretics etc

Question 7

WHAT IS PRIMARY HYPERPARATHYROIDISM

Answer 7

CHARACTERISED BY RAISED CALCIUM AND NON SUPPRESSED PTH
- 1:500 general population
- Increasing age, F>M
- 90% due to solitary parathyroid adenoma, carcinoma is extremely rare
- 5% of all gland hyperplasia due to MEN1 and chronic renal disease.
- Complications include nephrolithiasis, osteoporosis, neuromuscular and ?
increased CVD mortality
- Rate of disease progression is variable -> may be minimal in post-menopausal women with mild hypercalcemia.

Question 8

Hwo do we manage primary hyperparathyroidism?

Answer 8

• observe if mild, asymptomatic biochemical disease in the elderly female.
• HRT? in post menopausal women
• At risk patients: parathyroidectomy
• Interim medical therapy for moderate to severe hypercalcemia (>3.5,mmol)
• Rehydration, bisphosphonates
• Calcimimetric agents (calacalcet) for PTH mediated hypercalcemia

Question 9

What are indications for surgeyr in PHPT

Answer 9

Overt risk of complications: nephrolithiasis, renal impairment, parathyroid bone disease, neuromuscular disease, previous life threatening hypercalcemia

High risk of complications: serum calcium >3mmol/L, urine calcium >10mmol/day, reduced BMD

Other: age <50

Question 10

WHAT ELSE WOULD YOU CONSIDER IN APPARENT PHPT

Answer 10

• familial hypocalciuric hypercalcemia

- parathyroid hyperplasia (5%) PHPT (sporadic, MEN, familial isolated hyperparathyroidism)

Question 11

What is FHH?

Answer 11

Disorder of extracellular Ca2+ sensing due to CaR mutations (multiple described). Characterised by lifelong mild-moderate (1.5mmol/l) asymptomatic hypercalcemia
- Elevated set point for calcium regulation PTH release (ie. for any given level of serum calcium, FHH patients have higher concentrations of PTH than normal.
– Autosomal dominant, high penetrance and significant phenotypic variability
– Hypercalcaemia accompanied by low urinary calcium and inappropriately normal
serum PTH Serum 25OHD, 1,25OH2D3 normal
– Generally considered benign (no nephrolithiasis), however older patients with FHH show high prevalence of chondrocalcinosis, possible increased risk of pancreatitis

Question 12

20% of patients with advanced malignancy can experience hypercalcemia of malignancy. why?

Answer 12

• Osteolytic metastases (breast and non-small cell lung cancer)
  ::: Local cytokine mediated (TNF, IL-1)
• Osteoclast activating factors (multiple myeloma, lymphoma)
  ::: Circulating cytokine mediated (TNF, IL-1, IL-6)
• Excess calcitriol (1,25 Vit D) (lymphoma and granulomatous disease)
• PTH-related peptide (PTHrP) (particularly non-metastatic solid tumours)

Question 13

PTH related peptid (PTHrP)

Answer 13

• PTHrP Has N terminal homology with PTH.
  : Developmental hormone (cartilage, breast)
  : Placental function, lactation
  : humoral hypercalcaemia of malignancy (80% of hypercalcemia associated with solid tumours)

– PTH / PTHrp receptor mediated PTHrP action

– PTHrP is not identified by the PTH assay

Question 14

How do you treat non PTH mediated hypercalcemia

Answer 14

Treatment: obserrve if mild biochemical disease and treat underlying disorder

• interim medical therapy for moderate - severe hypercalcemia (>3.5mmol/L calcium)
• rehydration and bisphosphonates
• Saline diuresis with frusemide
• Blind CaR and suppress the PTH release
• Glucocoritcoids- granulomatous of lymphomatous hypercalcemia
• Calcitonin dialysis, mithramycin, gallium nitrate etc.

Question 15

What causes:

• secondary hyperparathyroidism?
• tertiary hyperparathyroidism?

Answer 15

Secondary HPT: decreased calcium results in an appropriate rise in PTH.
Tertiary HPT: chronic parathyroid overstimulation in renal disease leads to parathyroid hyperplasia and hypercalcemia

Question 16

What is Multiple Endocrine Neoplasia type 1? what are other names for it?

Answer 16

MEN1, Wermer’s Syndrome, MEA1

1. AUTOSOMAL DOMINANT disease: tumour suppressor gene on chromosome 11q; high penetrance (95% by the age 30)
2. 2 per 100,000
3. Identified in all major racial groups
4. Considered to have a PPP PHENOTYPE:
   - PARATHYROID
   - ENTEROPANCREATIC
   - PITUITARY neoplasia

Question 17

Spectrum of the MEN1 Phenotype

Answer 17

Large- can invade pretty much anything and everything.

Parathyroid Pancreatic Pituitary Adrenal Gastroduodenal Thymus Bronchus Thyroid Subcutaneous Skin Smooth muscle CNS

Question 18

What is the MEN1 gene?

Answer 18

Tumour suppressor gene on chromosome 11q with high penetrance.
encodes a 610 aa product that behaves as a transcriptional co represor for genes associated with cell growth.
- >80% of mutations predict a loss of function (c/wTSG): >200 mutations identified to date, some intronic
- Numerous polymorphisms not associated with MEN1
- 10-20% of families do NOT have an identifiable mutation

Question 19

What is the MEN1 disease spectrum?

Answer 19

Endocrine Tumours: benign or malignant

Non endocrine mesenchymal tumours

Question 20

What is the MEN1 disease spectrum?

- a: benign and malignant endocrine tumours

Answer 20

Benign

• Parathyroid hyperplasia >95%
• Pituitary Adenoma 20-50%
• Adrenal macronodular hyperplasia 25%

Malignant potential

• Gastro-enteropancreatic NET’s (gastrin, glucagon) ; 30-50%
• “non functioning” pancreatic adenoma 50-80%
• Bronchial carcinoid <5%

Question 21

What is the MEN1 disease spectrum?

b: non endocrine mesenchymal tumours

Answer 21

• skin (angiofibroma, collagenomas, macules) >80%

- leiomyomas (uterine, oesophageal, lung) ?20%

Question 22

How do we diagnose MEN1

Answer 22

Familial :
- MEN1 gene identified, family history and one characteristic disorder, obigate carrier

Non familial MEN1:

• synchronous and metasynchronous presence of 2 or more characteristic disoders
• a well defined family history of mutation is absent

Question 23

Hyperparathyroidism in MEN1

Answer 23

hyperparathyroidism is usually the FIRST MANIFESTATION in MEN1
Develops in >95% of gene characters by the age of 30.
Early treatment is important for even MILD hypercalcemia.

Question 24

‘non functioning’ pancreatic adenoma in MEN1

Answer 24

• Develop in up to 70% of gene carriers (up to 40% by age 20)
• Commonly multi-focal and clinically
• Resect if large or rapidly enlarging

Question 25

Hypergastrinaemia in MEN1

Answer 25

Rare <30, but effects at least 50% of patients with MEN1 -multifocal duodenal tumours (pancreatic/gastric tumours) Clinical ZES** in 25% of MEN1: severe peptic ulcer disease, metastatic malignancy SECRETIN TEST ***Zollinger-Ellison syndrome (ZES) is an endocrinopathy characterised by gastrin-secreting tumours, which cause multiple, refractory and recurrent peptic ulcers in the distal duodenum and proximal jejunum

Question 26

What are your gut hormones and what do they secrete?

Answer 26

HYPERGASTREMIA ``` D Cells (stomach / pancreas) - Somatostatin G Cells (stomach) - Gastrin (release of histamine by gastrin causes H+ release) I Cells (small intestine) - Cholecystokinin (CCK) Gut Hormones K Cells (small intestine) - Gastric inhibitory polypeptide (GIP) L Cells (small intestine) - Glucagon-like peptide-1 (GLP-1) S Cells (small intestine) - Secretin ```

Question 27

Insulinoma in MEN1

Answer 27

= tumour of the pancreas uncommon (<5%) Rare after age 30 symptomatic presentation 72 hour fast typically single adenoma cured by adenomectomy in most people Whipples triad: Symptoms known or likely to be caused by hypoglycemia A low plasma glucose measured at the time of the symptoms Relief of symptoms when the glucose is raised to normal

Question 28

What are some causes of hypoglycemia in adults?

Answer 28

(ill or medicated individual) 1. Drugs: insulin, alcohol 2. Critical illness: hepatic, renal, cardiac failure 3. Hormone deficiency: cortisol, glucagon and epinephrine (seemingly well individual) insulinoma

Question 29

Pituitary Neoplasia in MEN1

Answer 29

Prolactinoma (10-20%) and non- functioning adenoma (10%) are the most frequent manifestations Uncommonly TSH, GH, and ACTH Up to one third of gene carriers develop pituitary tumours Conventional management appropriate: Dopamine agonists. Surgery. Observation Behavior of more aggressive than sporadic disease

Question 30

Adrenal Lesions

Answer 30

Develop in up to 1/3 of patients typically occurs in association with overt pancreatic adenoma clinically non functioning and typically benign (MNH)

Question 31

How do you manage MEN1

Answer 31

Manage as a CHRONIC MULTISYSTEM DISEASE 1. REGULAR SCREENING FOR - PHPT - Enteropancreatic tumour - Pituitary disesae - Intrathorasic malignancy - Other (CVD risk factors) 2. TREAT DISEASE PHENOTYPES AS IDENTIFIED 3. RISK FACTOR MODIFICATION TO PREVENT COMPLICATIONS: - calcium - gastrin - onventional CVD risk factors

Question 32

In summary, what are the three organs effected in MEN1?

Answer 32

Parathyroid Pituitary pancreas

Question 33

In MEN1, what happens to the parathyroid?

Answer 33

hyperparathyroidismis the most common sign of this disorder. Hyperparathyroidism disrupts the normal balance of calcium in the blood, which can lead to kidney stones, thinning of the bones (osteoporosis), high blood pressure (hypertension), loss of appetite, nausea, weakness, fatigue, and depression.

Question 34

in MEN1, what happens to the pituitary?

Answer 34

Neoplasia in the pituitary gland can manifest as prolactinomas whereby too much prolactin is secreted, suppressing the release of gonadotropins, causing a decrease in sex hormones such as testosterone. Pituitary tumor in MEN1 can be large and cause signs by compressing adjacent tissues.

Question 35

In MEN1 , what happens in the PANCREAS**

Answer 35

Pancreatic tumors usually form in the beta cells of the islets of Langerhans, causing over-secretion of insulin, resulting in low blood glucose levels (hypoglycemia). However, many other tumors of the pancreatic Islets of Langerhans can occur in MEN1. One of these, involving the alpha cells, causes over-secretion of glucagon, resulting in a classic triad of high blood glucose levels (hyperglycemia), a rash called necrolytic migratory erythema, and weight loss. Another is a tumor of the non-beta islet cells, known as a gastrinoma, which causes the over-secretion of the hormone gastrin, resulting in the over-production of acid by the acid-producing cells of the stomach (parietal cells) and a constellation of sequelae known as Zollinger-Ellison syndrome. Zollinger-Ellison syndrome may include severe gastric ulcers, abdominal pain, loss of appetite, chronic diarrhea, malnutrition, and subsequent weight loss. Other non-beta islet cell tumors associated with MEN1 are discussed below.

Question 36

IN summary, which three endocrine organs are usually affected in MEN1?

Answer 36

Parathyroid, Pituitary Pancreas

Question 37

What happens to the PARATHYROID In MEN1?

Answer 37

Hyperparathyroidism disrupts the normal balance of calcium in the blood, which can lead to kidney stones, thinning of bones (osteoporosis), high blood pressure (HTN), loss of appetite, nausea, weakness, fatigue and depression.

Question 38

What happens to the PITUITARY IN MEN1

Answer 38

Neoplasia in the pituitary gland can manifest as prolactinomas whereby too much prolactin is secreted (prolactinoma), suppressing the release of gonadotropins, causing a decrease in sex hormones such as testosterone. Pituitary tumour in MEN1 can be large and cause signs by compressing adjacent tissues