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Endocrinology > Biochemistry of Neuroendocrine Tumours > Flashcards

Biochemistry of Neuroendocrine Tumours Flashcards

1
Q

What are neuroendocrine tumours (NETs)?

A

Very rare tumours that originate from Neuroendocrine cells that can happen almost anywhere in the body

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2
Q

What is the role of neuroendocrine cells?

A

They form a link between the nervous system and endocrine system
Signal comes from nerve cells and stimulate the release of hormones (e.g. Adrenaline from the adrenal medulla)

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3
Q

Where do NETs form commonly?

A

GI tract, pancreas, lungs, and adrenal medulla

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4
Q

How fast do NETs form? Are they malignant or benign? Do they show symptoms?

A

-Either very fast or very slow (WHO grading 1-3)
-Can be either malignant or benign
-Asymptomatic or can have a wide range of symptoms

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5
Q

What are the 3 most common NETs?

A
  • Carcinoid Tumours
  • Pheochromocytoma & Paraganglioma
  • Pancreatic Neuroendocrine Tumours/Islet Cell Tumours
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6
Q

How fast do Carcinoid Tumours grow? Where do they usually grow? What can they make?

A
  • Tend to be slow
  • GI and broncopulmonary system, thymus, pancreas, ovaries and prostate
  • Range of endocrine peptides (Serotonin, ACTH, etc)

-Incidence is very low (2-3 per 100,000) (slightly more common in F)
-More common in older age (55-70)

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7
Q

How are carcinoid tumours classified?

A

Based on location:
* Foregut CT: Lungs, bronchus, stomach, proxumal duodenum, pancreas
* Midgut CT: Latter part of the duodenum until the right colon
* Hindgut CT: Rectum and genitourinary tract

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8
Q

What is Serotonin? Where is it produced? What’s its function?

A
  • 5-Hydroxytryptamine (5-HT)
  • Neurotransmitter made within CNS and GI tract. Most is found in the gut, but also in platelets in the brain
  • Mood and bowel function regulation. Aids motility, influences satiety, and increases blood flow and fluid secretion
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9
Q

How is Serotonin produced?

A

1) Tryptophan
(Tryptophan hydroxylase)
2) 5-Hydroxytryptophan (5-HTP)
(Aromatic Acid Decarboxylase)
3) 5-Hydroxytryptamine (Serotonin, 5-HT)

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10
Q

How is Serotonin metabolised?

A

1) 5-Hydroxytryptamine (Serotonin, 5-HT)
(Monoamine Oxidase (MAO))
(Aldehyde Dehydrogenase (AD))
2) 5-Hydroxyndolacetic acid (5-HIAA)
-98% of Serotonin gets converted into 5-HIAA

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11
Q

Why is tryptophan metabolism important in each carcinoid tumour?

A

-Fore-gut CT: Some have the decarboxylase
-Mid-gut CT: They have the decarboxylae
-Hind-gut CT: Most don’t have it

-Many carcinoid tumours lack a decarboxylase enzyme and thus develop elevated 5-HTP rather than serotonin. Therefore, also lack 5-HIAA

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12
Q

What is Chromogranin A (CgA) and what’s its role in carcinoid tumours?

A

-Protein released by neuroendocrine cells (NEC). Grains are a family of peptides found inside secretory granules
-NETs almost always produce an increased amount of CgA
-Not specific for Carcionid Tumours

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13
Q

What are some signs/symptoms of carcinoid tumours?

A

-Often asymptomatic
-Vague and dependent on tumour location and tumour mass:
* Lungs; shortness of breath
* GI tract; abdominal pain, nausea, rectal bleeding

  1. Flushing and diarrhea (>75%)
  2. Heart valve problems (Carcinoid heart disease)
  3. Cramping, pellagra, arthritis
  4. Wheezing, nausea, vomiting
  5. Effects on “other peptides”

Symptoms often mark the metastatic stage of the disease

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14
Q

What is Carcinoid Syndrome and what’s its cause?

A

-Group of symptoms cause by CTs
-Many CTs won’t have Carcinoid Syndrome
-Caused by excess vasoactive peptides (usually Serotonin)

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15
Q

Carcinoid Syndrome: What 2 broad groups of individuals are affected?

A

-Those with carcinoid tumours that drain directly into the blood
-Those with metastatic disese

This is where biochemical testing is most effective

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16
Q

What biochemical investigations can be performed for Carcinoid tumours/syndrome?

A

-Urinary and plasma 5-HIAA
-Serum Chromogranin A (CgA)
-Whole blood (platelet 5-HT) and urine Serotonin
-+/- Catecholamines, ACTH, IGF-1, etc

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17
Q

What does 5-HIAA stand for?

A

5-HydroxyIndoleAcetic Acid

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18
Q

What is 5-HIAA? How is it excreted? How is it measured?

A

-It’s a metabolite of Serotonin
-It’s excreted in urine
-Measured by HPLC

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19
Q

What things should a patient avoid before measureing Urine 5-HIAA?

A
  • Foods w high serotonin/tryptophan content like bananas, avocados, kiwis, melons, pineapples, etc
  • Nuts
  • Tomatoes
  • Caffeine
  • Paracetamol, aspirin, anti-histamines, and cough syrups
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20
Q

How is the urine 5-HIAA sample collected and mantained?

A

-24h urine collection (can also be spot)
-Sample acidified to pH 4 with glacial acetic acid
-It’s stable for >48h at 4C

21
Q

What does high 5-HIAA mean? Can you rule out Carcinoid Tumours if results come back normal?

A

-High 5-HIAA is associated with carcinoid tumours
-Normal results usually rule out carcinoid SYNDROME
-But cannot rule out carcinoid TUMOURS since not every carcinoid tumour results in carcinoid syndrome

Carcinoid syndrome is associated with high 5-HIAA, but since carcinoid tumours can happen without the syndrome, you might have a tumour with normal 5-HIAA

22
Q

How do you collect a CgA sample?

Does the patient need fasting? What medications to avoid?

A

-Fasting
-No PPIs for at least 2 weeks
-Serum or plasma
-Spun and frozen

PPI = Proton Pump Inhibitor

23
Q

What could cause a false positive in CgA measurements?

A
  • PPIs, H2 Receptor Agonists, Atrophic Gastritis
  • Impaired renal and liver function
  • Unterated HTN, RA, Heart Disease, IBS, IBD, Pernicious Anaemia

Atrophic Gastritis = enterochromaffin cells produce CgA

24
Q

What NETs elevate CgA?

A

-Most of em’
-Carcinoids, Phaeo, Neuroblastomas, MTCs, etc

25
Q

Can other tumours elevate CgA?

A

-Yup. Some that aren’t even derived from neuroendocrine tissue can
-Small-cell lung carcinoma and PCa

idk what PCa stands for

26
Q

Is CgA sensitive for Carcinoid Tumours? When are CgA measurements most useful? Does CgA levels say anything about tumour mass?

A

-90% sensitivity for carcinoid tumours
-Useful for hindgut carcinoids since they have normal serotonin and 5-HIAA but elevated CgA
-CgA has a relatively linear relation with tumour mass

27
Q

What are the characteristics of the 3 tests for Carcinoid tumours?

Sensitive/specific for what?

A
  • Urine 5-HIAA is specific for carcinoid syndrome but not sensitive for carcinoid tumours
  • Cga is sensitive for carcinoid tumours but not specific for carcinoid tumours (other things/tumours can elevate it)
  • Urine serotonin is useful dor carcinoid tumours lacking decarboxylase (rarely needed)
28
Q

When is 24h Urinary serotonin useful?

A

In subset of tumours where:
* Serotonin and 5-HIAA remain low
* +/- CgA
* Elevated 5-HTP

Elevated 5-HTP leads to elevated Serotonin which passes thru the kidneys, so there’s a subset of tumours in which urinary serotonin is elevated but blood serotonin is normal

29
Q

What are the advantages/disadvantages of 24h Urinary Serotonin measurements?

A

Advantages:
* Greatest sensitivity for Serotonin, 5-HIAA, and CgA negative tumours (Many hindgut tumours and some foregut tumours)
* Greater specificity for carcinoid tumours than CgA
Disadvantages:
* Often poor sensitivity for other carcinoids
* Often unecessary if CgA is positive and you have a confirmed carcinoid tumour

30
Q

What are Paragangliomas and Phaeochromocytomas? Where do they occur? What symptom are they known to cause? What do they produce?

A

-Rare tumours of the sympathetic nervous symptom
* Phaeo = Adrenal
* PGL = Extra Adrenal
-HTN
-Norepinephrine, epinephrine

31
Q

Which are more common, Phaeos or PGLs?

A

~85% are Phaeo

32
Q

What is PNMT? What does it do? Where is it found?

A

-Phenylethanolamine N-MethylTransferase
-Converts Adrenaline into Metanephrine (metabolite)
-Found mostly in the adrenals

33
Q

What does it mean if metanephrine is raised due to a tumour?

A

-The tumour must be coming from the adrenals (Phaeo)

34
Q

What does it mean if normetanephrine is raised due to a tumour?

A

-It could be either Phaeo or PGL

35
Q

When should you suspect a Phaeo/PGL?

A
  • HTN (especially severe and in sudden fits)
  • Adrenal incidentalomas (random adrenal mass)
  • Familiar history (known mutations or familial syndromes like Von Hippel-Lindau, MEN Type II)
36
Q

Why should Pheos/PGLs be detected?

A
  1. Small significant percentage are malignant
  2. Most hypersecrete catecholamines and prolonged exposure to these can cause cardiac morbidity
  3. Risk of HTN crisis
  4. Identification of mutations can help family members get screened early, reducing chance of morbidity
  5. Can be often cured if identified
37
Q

What 2 biochemical tests are done for Pheo/PGL?

A
  1. Plasma free fractionated metanephrines
  2. 24h urinary fractioned metanephrines
38
Q

What role does biochemistry play in Pheo/PGL detection?

What is measured and where?

A

-Vast majority of catecholamines can be detected in blood or urine
-In normal situations, these metabolites are produced episodically
-In tumours, they’re produced continuously

39
Q

How are plasma Free Mets. sampled?

A

-Fasting
-Plasma mets are taken on ice, then frozen
-Patients lay down facing upwards (supine position)

40
Q

How are Urinary Mets. sampled?

A

-24h urine acidified collection
-Tot Fractioned Metanephrines are measured (Tot metanephrines, Tot Normetanephrine), but recently Free Fractioned Metanephrines have been shown to be just as good

41
Q

How are Metanephrines in both Urine and Plasma measured?

What technique is used?

A

-LC-MS or HPLC with electrochemical detection (ECD)
-NOT IMMUNOASSAYS!!!

42
Q

What do you do if the sample shows elevated Metanephrines?

What is the next step?

A

-All + results should be followed up
-Repeat testing after researching patient’s medications
-Or direct referral to specialist

43
Q

How are positives interpreted for Metanephrines?

A

-Since these tumours are rare and there are other things that can rise Mets, most elevated results don’t mean that you have a Phaeo/PGL
-BUT if both Metanephrine and Normetanephrine are elevated, you’re likely to have an Adrenal Pheo
-Elevations in either metabolite >3 the upper limit are highly suggestive

44
Q

How do you sort false + from true + in Pheo/PGL?

A

-Repeat sampling in supine position
-Many results will go back to normal
-If the repeated sampling shows elevated results still, do a Clonidine Suppression Test

Others often use a combo of CgA and Urinary Mets to help establish Dx

45
Q

What is Clonidine? What does it do?

A

-It’s an alpha-adrenoreceptor agonist that inhibits Norepinephrine in normal individuals, but not in tumours

46
Q

How do you do a Clonidine Suppression Test? What results are supportive of a tumour?

A

-Patients lay down for 30min and baseline plasma Norepinephrine is taken
-Clonidine is administered and 3h later a second sample is taken
-If both results are elevated or if the second sample doesn’t suppress norepinephrine by >40%, it’s supportive of a tumour

47
Q

Once Pheo/PGL is confirmed biochemically, what does the follow-up consist of?

What other Dx procedure is done?

A

-Imaging to detect the location of the tumour
-CT is the primary imaging modality
-If CT can’t be done (children, pregnant women), MRI is fine

Occasionally more specialist testing is needed, like MIBG scanning (radio-isotope is taken up by the tumour)

48
Q

If your patient is positive for Pheo/PGL, and imaging is done and they’re being treated, what’s an important thing left to do?

Hint: What is 1/3 of the causes of Pheo/PGL?

A

Genetic testing:
* PGL patients should get genetic testing for SDH mutations
* All metastatic tumours identified should have testing for SDH-B mutations

49
Q

How are patients with Pheo/PGL managed?

A

-Pre-op blockade with alpha-blockers for 1-2 weeks
-Removal of tumour
-Post-treatment Plasma or Urine Mets monitoring to check for recurrence and confirm successful removal of tumour

Endocrinology (4 decks)

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