Biogenic Amines Flashcards
Basic physiology: examples and sites of biosynthesis, significance
Naturally occurring, biologically active amines - many are neurotransmitters and hormones
Examples: catecholamines, serotonin, histamine
Sites of biosynthesis:
- catecholamines –> dopaminergic and noradrenergic neurons, sympathetic nerves, chromaffin cells of adrenal medulla, paraganglia
- serotonin –> CNS serotonergic neurons, pineal gland, some peripheral endocrine tissues
Clinical significance:
- hormones and metabolites measured in blood and urine –> useful for NE tumour Dx e.g. pheochromocytoma, paragangliomas, neuroblastoma, carcinoids
Catecholamine metabolism
Tyrosine --> DOPA --> Dopamine then ----> Homovanillic acid (HVA) or --> NA --> Adrenaline by PNMT which is specific to adrenal glands (phenylethanolamine-N-methyltransferase)
NA –> Normetanephrine –> VMA (vanillylmandelic acid)
A –> Metanephrine –> VMA
Serotonin metabolism
Tryptophan –> 5-hydroxytryptophan –> Serotonin —-> 5-HIAA (5-hydroxyindoleacetic acid)
Chromaffin cell tumours: Phaeochromocytoma vs Paraganglioma
MAIN DIFFERENCE IS THE SITE
Phaeochromocytoma
- arising from adrenomedullary chromaffin cells
- commonly produces one or more catecholamines
- most are biochemically active
- 80-85% chromaffin cell tumours
Paraganglioma
- arising from extra-adrenal chromaffin cells of sympathetic or parasympathetic NS
- those from parasympathetic NS don’t secrete catecholamines
- 15-20% chromaffin cell tumours
Phaeochromocytoma prevalence, aetiology
0.8 per 100000 person-years
Peak occurrence in 40-50s
(along with paragangliomas) are in 0.2-0.6% of patients with HT
1.7% of children that have HT
5% of patients with adrenal incidentalomas
Aetiology
- most are sporadic
- 10% familial (PPGL likely bilateral; younger onset) –> associated syndromes e.g. VHL, MENII, NF1
Secretion of excessive NA, A, NM, M and VMA
Phaeochromocytoma clinical features
10% extra-adrenal (i.e. paraganglioma)
10% bilateral
10% malignant
10% secrete adrenaline/dopamine (90% NA)
Symptoms and signs:
- PAROXYSMAL when present
- classic triad: episodic headache, sweating, tachycardia/palpitations
- paroxysmal HT (5-15%) – atypical –> young, resistant to antihypertensives, complications (nephropathy, retinopathy, encephalopathy)
- atypical DM
- phaeochromocytoma crisis (hyper/hypotension, hyperthermia, mental status changes, other organ dysfunction)
When to investigate for phaeochromocytoma and paraganglioma
- signs and symptoms or young onset HT
- symptoms provoked by drugs e.g. D2 receptor antagonists, beta blockers, sympathomimetics
- incidentaloma
- hereditary predisposition or syndromic features e.g. MTC + primary hyperPTH or muocutaneous neuromas (MENII), hemangioblastoma/retinal angioma/clear cell RCC/pancreatic NE tumours (VHL), neurofibromas/multiple cafe au lait spots (NF1)
- previous hx of PPGL
First line lab tests for phaeochromocytoma: available tests, sensitivity/specificity, false positives
- Plasma free or urine total metanephrines
a) 24hr urine:
- can measure Cr (ensure complete collection), NA, A, **fractionated NM, M, VMA
–> NA/A >2x, NM/M >2x, VMA >3x = +ve
Sensitivity and Specificity:
- -> most sensitive if measure at onset of “attack”
- -> fractionated NM/M highest specificity
- -> r/o false positives
- stop medications for 2 wks e.g. labetalol (decrease reuptake), TCA, MAOi (increase release/ decrease metabolism), clozapine (decrease reuptake), levodopa (metabolised to catecholamines)
- major physical stress e.g. hypoBG, stroke, raised ICP
- OSA (low PaO2 stimulates SNS)
b) Plasma catecholamines
- fasting, supine (posture-dependent), draw blood from indwelling catheter in place >30 min
- false positives same as urine + diuretics (change in plasma volume), smoking
- epinephrine suitable for CKD/ ESRD
c) Plasma free metanephrines
- highest sensitivity but relatively new and not widely available
- not posture dependent
- produced by tumour continuously
- levels remain relatively unaffected during SNS stimulation
- urine VMA/M/NM are from catecholamines produced other than tumour
- false positive: paracetamol, ESRD
- high plasma metanephrine:catecholamines also makes tumour probable
- Locate tumour with imaging if highly probable
- CT, MRI, MIBG scan
Suppression Test for Phaeochromocytoma
Clonidine suppression test
- overnight fasting, empty bladder and take 0.3 mg PO at 2100, collect urine from 2100-0700
- indication: strong clinical suspicion of phaeochromocytoma with borderline increase in catecholamines (after eliminating medications/causes of false +ve)
- precaution: stop anti-HT drugs 1wk prior and during
- principle: normal physiological catecholamine is suppressed by clonidine but autonomous tumour isn’t
- risk: profound drop in BP (but safer than glucagon stimulation)
Interpretation
–> normal: NA <60 nmol/mmol Cr and A <20 nmol/mmol Cr
==> anything above = not suppressible = phaeochromocytoma
Stimulation Test for Phaeochromocytoma
Glucagon stimulation test
- overnight fasting, take blood –> 1mcg glucagon IV bolus injection –> take blood 2 min after and check BP at 1 min intervals from 10-20 min after injection
- indication: strong clinical suspicion of phaeochromocytoma with borderline increase or normal catecholamines
- precaution: refrain anti-HT drugs 48hrs prior to and during
- principle: stimulate catecholamine secretion from tumour (stimulate symptoms)
- risks: extreme rise in BP (need phentolamine IV 10 mg standby)
Interpretation:
- NA peak>2000 pg/ml or >3x increase over baseline
Neuroblastoma origin, prevalence, sites, presentation, screening/Dx
Malignant tumour from neuroblasts that has capacity to synthesise and secrete catecholamines
- > almost exclusively in children
- MC malignancy in 1st yr of life
Most are sporadic (1-2% familial)
65% intra-abdominal (adrenal gland or upper abdomen)
60% extra-adrenal
Presentation:
- tumour mass
- compression effects
- haematological abnormalities from BM involvement
- HT is rare
Screening and Dx:
- 24hr urine VMA and HVA (high specificity; plasma concentration too low)
Prognosis poor if VMA:HVA <1, high neuron-specific enolase/LDH/ferritin
Carcinoid Tumour
Derived from enterochromaffin cells
Most frequently found in GI (64%) and respiratory tract (28%)
Develops in all age groups, mean age 63
Most patients asymptomatic until liver metastasis (carcinoid syndrome)
==> vasoactive substances not adequately metabolised by the liver –> enters systemic circulation
- bowel obstruction, abdominal pain, flushing, diarrhoea, wheezing, dyspepsia, hypotension, RHF
Classification of Carcinoid
Foregut
- bronchus, lung, stomach, duodenum, pancreas
- -> secrete 5-hydroxytrytophan and histamine
Midgut
- ileum, jejunum, appendix, proximal colon
- -> large quantities of serotonin
Hindgut
- rectum, distal colon
- -> no serotonin or 5-hydroxytryptophan secretion
Lab investigation of carcinoid tumours
24hr urine 5-HIAA (plasma concentration too low to analyse)
- preferably start collection when patient symptomatic
- midgut carcinoid usually >10x increase in 5-HIAA
False positive: - avoid 3 days prior and during
- serotonin-rich foods e.g. bananas, pineapples, chocolate, kiwi, cough medications with guaifenesin
- smoking may cause slight elevation due to nicotine stimulated release
False negative:
- suppressed 5-HIAA: alcohol, aspirin
———————————
Elevated ALP (cholestatic picture) due to SOL in liver = metastasis
(extra) plasma vs urine sampling
Plasma –> low conc can make analysis difficult (blood collections require time, more convenient for patients, better regulated sampling, influences of diet easily controlled, applicable to ESRD)
Urine –> well established and widely available, analysis easy, easy to implement, inconvenient for patients, unreliable collections, difficult to control diet and daily life influences on sympathoadrenal function, not suitable for ESRD
