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PATHOLOGY CAM304 > MEN 1 Endocri JB > Flashcards

MEN 1 Endocri JB Flashcards

(38 cards)

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1
Q

How much calcium would you consume from the 1000g intake

A

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

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2
Q

how does PTH mediate calcium homeostasis?

A

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

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3
Q

Explain CALCIUM HOMEOSTASIS

A

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
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4
Q

What are the clinical manifestaitions of hypercalcemia

A

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

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5
Q

how do we classify hyperparathyroidism?

A

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)
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6
Q

How do we assess hyperparathyroidism?

A

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
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7
Q

WHAT IS PRIMARY HYPERPARATHYROIDISM

A

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.

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8
Q

Hwo do we manage primary hyperparathyroidism?

A
  • 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
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9
Q

What are indications for surgeyr in PHPT

A

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

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10
Q

WHAT ELSE WOULD YOU CONSIDER IN APPARENT PHPT

A
  • familial hypocalciuric hypercalcemia

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

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11
Q

What is FHH?

A

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

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12
Q

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

A
  • 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)
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13
Q

PTH related peptid (PTHrP)

A
  • 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

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14
Q

How do you treat non PTH mediated hypercalcemia

A

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.
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15
Q

What causes:

  • secondary hyperparathyroidism?
  • tertiary hyperparathyroidism?
A

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

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16
Q

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

Study These Flashcards
A

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
17
Q

Spectrum of the MEN1 Phenotype

Study These Flashcards
A

Large- can invade pretty much anything and everything.

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

18
Q

What is the MEN1 gene?

Study These Flashcards
A

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

19
Q

What is the MEN1 disease spectrum?

Study These Flashcards
A

Endocrine Tumours: benign or malignant

Non endocrine mesenchymal tumours

20
Q

What is the MEN1 disease spectrum?

- a: benign and malignant endocrine tumours

Study These Flashcards
A

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%
21
Q

What is the MEN1 disease spectrum?

b: non endocrine mesenchymal tumours

Study These Flashcards
A
  • skin (angiofibroma, collagenomas, macules) >80%

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

22
Q

How do we diagnose MEN1

Study These Flashcards
A

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
23
Q

Hyperparathyroidism in MEN1

Study These Flashcards
A

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.

24
Q

‘non functioning’ pancreatic adenoma in MEN1

Study These Flashcards
A
  • 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
25
Hypergastrinaemia in MEN1
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
26
What are your gut hormones and what do they secrete?
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 ```
27
Insulinoma in MEN1
= 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
28
What are some causes of hypoglycemia in adults?
(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
29
Pituitary Neoplasia in MEN1
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
30
Adrenal Lesions
Develop in up to 1/3 of patients typically occurs in association with overt pancreatic adenoma clinically non functioning and typically benign (MNH)
31
How do you manage MEN1
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
32
In summary, what are the three organs effected in MEN1?
Parathyroid Pituitary pancreas
33
In MEN1, what happens to the parathyroid?
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.
34
in MEN1, what happens to the pituitary?
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.
35
In MEN1 , what happens in the PANCREAS**
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.
36
IN summary, which three endocrine organs are usually affected in MEN1?
Parathyroid, Pituitary Pancreas
37
What happens to the PARATHYROID In MEN1?
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.
38
What happens to the PITUITARY IN MEN1
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

PATHOLOGY CAM304 (16 decks)

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