Multiple endocrine neoplasia type 1

This diagnosis is typified by hyperparathyroidism, pituitary tumours and pancreatic tumours, and may be confirmed by finding a mutation in the MENIN gene.

Baseline investigations - in all patients

Full blood count

Useful indicator of general health and underlying disease.

Urea and electrolytes

Hyperkalaemia may occur with glucocorticoid deficiency. Hypokalaemic acidosis may occur with severe diarrhoea, for example due to VIPoma.

Hyponatraemia may occur with salt and water depletion.

Liver function test

Useful indicator of general health and possible malignancy.

Bone profile

Hypercalcaemia is usually present at diagnosis and almost always indicates parathyroid disease, though it may also complicate neuro-endocrine tumours.

Fasting glucose and HbA1c

These are useful baseline measurements.

Hypoglycaemia raises the possibility of an occult insulinoma, and may occur with glucocorticoid deficiency or metastatic disease.

Many pancreatic neuro-endocrine tumours lead to glucose intolerance, for example glucagonomas.

Parathyroid hormone

Useful baseline screen for parathyroid pathology and essential if an elevated calcium is detected.

Fasting gut hormones

Gut hormones should be documented at diagnosis and annually thereafter unless clinically indicated more frequently.

This should be performed after a 12 hour fast. This test usually includes chromogranin A and B, vasoactive intestinal peptide VIP, somatostatin, glucagon, gastrin, pancreatic polypeptide PP, neurotensin, with a concurrent sample for urea, electrolytes and calcium testing.

Proton pump inhibitors need to be stopped for at least two weeks, and H2 (histamine 2 receptor) antagonists stopped for at least three days prior to testing serum gut levels in the screening of pancreatic disease.

Baseline pituitary function


Prolactin

This is the most useful blood test to screen for pituitary pathology, as prolactinomas are the most frequent pituitary tumour encountered in MEN1, and elevated prolactin also occurs with non-functioning tumours due to loss of dopaminergic inhibition.

Elevated prolactin levels should always prompt a medication review, as well as the PEG precipitation test to determine whether this is biologically active or the inactive 'macroprolactin'.


9am cortisol

Due to the circadian rhythm of ACTH release, cortisol reserve is best assessed early morning (or on waking in patients with irregular hours, for example shift workers). Ensure patients have stopped sex steroid therapy, for example HRT or the combined oral contraceptive pill for six weeks prior to test. Estrogen replacement therapy leads to elevation of cortisol binding globulin and hence serum cortisol and so is difficult to interpret. 

Levels above 590nmol/l exclude glucocorticoid deficiency. Patients with levels below this may require formal assessment for ACTH reserve in the presence of pituitary disease with an insulin stress test or glucagon test.

Cortisol excess is not tested for in this way, and if suspected requires urinary free cortisols and a dexamethasone suppression test.


Thyroid stimulating hormone, free thyroxine

It is essential to assess levels of both thyroxine and thyroid stimulating hormone (TSH) in pituitary patients since a normal TSH level is frequently associated with loss of thyroid function in this patient group.


Growth hormone, insulin like growth factor I

Recent guidelines recommend that a normal growth hormone (GH) and insulin like growth factor I (IGF-I) taken together form a useful screen for acromegaly. Elevation of either test taken with clinical suspicion mandates a formal GH suppression test with glucose tolerance testing.

Very low IGF-I levels alone are not diagnostic for GH deficiency but are a useful screen where this is suspected, and should be followed by a formal provocation test: insulin or glucagon stress tests LINKS.


Luteinising hormone, follicle stimulating hormone, sex hormone binding globulin, estrodiol/testosterone

Gonadotropin deficiency may be an early manifestation of pituitary disease.

This may be due to pituitary failure or a specific consequence of hyperprolactinaemia.

Chest radiograph

This should be performed at baseline as a screen for malignant disease, for thymic or bronchial lesions, and prior to considering surgery for parathyroid disease.

Further investigations - selected cases only

Electrocardiogram

ECG should be performed in all patients at baseline to document and confirm any arrhythmias or other changes.

MRI pituitary

This should be performed in all cases at diagnosis, but is not generally repeated unless a specific clinical indication arises.

CT pancreas

Abdominal CT or MRI scanning should be performed at baseline to document pancreatic anatomy and the presence of any visible pancreatic lesions.

This test is not usually repeated unless clinically indicated during long term follow up, for example with the development of new symptoms, rise in serum gut hormone levels, or to follow up previously documented lesions.

Consider referral to a clinical geneticist for counselling, DNA testing and family screening

If the diagnosis of MEN1 is clinically likely, for example in a patient with hyperparathyroidism and any other endocrine tumour, discuss genetic testing.

Vitamin D

Useful to document vitamin D levels to aid interpretation of serum calcium and PTH levels.

Supervised fast for insulin and c-peptide

Full investigation for possible insulinoma requires a supervised fast.

Calcium to creatinine clearance ratio

24hr urinary collection for calcium and creatinine is taken with a paired serum sample for calcium and creatinine.

This is essential at first presentation to exclude familial benign hypocalciuric hypercalcaemia, and is also useful to quantify renal excretion and as an indicator of the risk of renal stone formation.

Abdominal radiograph

Abdominal radiograph is a useful low cost screen to detect asymptomatic renal tract calcification.

Bone densitometry

With chronic hyperparathyroidism, this is useful to determine whether specific bony protection or treatment should be considered.

Neck ultrasound scan

In patients with confirmed primary hyperparathyroidism who are suitable for surgery, localisation is attempted using a combination of neck USS and MIBI. 

Where the results are concordant no further localisation is usually necessary and minimially invasive parathyroid surgery may be arranged, although multiple gland involvement is much more common in MEN.

Neck Sesta-MIBI scan

In patients with confirmed primary hyperparathyroidism who are suitable for surgery, localisation is attempted using a combination of neck USS and MIBI. 

Where results are discordant or unhelpful, selective venous sampling may aid localisation. 

Selective venous sampling of the neck

Where surgery is contemplated and localisation of the parathyroid is unclear, consider selective venous sampling of the neck and mediastinum.

Multiple sources of parathyroid hormone imply multiple gland disease. Surgery is less likely to be curative, and complete neck exploration may be considered.

Oesophagogastroduodenoscopy

If the patient complains of severe upper gastrointestinal symptoms suggestive of peptic ulcer disease, or has other warning features, for example anaemia or weight loss, direct visualisation of the upper gastrointestinal tract is essential.

Liver ultrasound

If there are any abnormalities of liver biochemistry or examination an ultra sound scan is required. When a neuro-endocrine tumour is suspected it is usual to proceed directly to CT scan to seek evidence of metastatic disease.

2x24hr urinary 5-hydroxyindole-acetic acid

5-hydroxyindole-acetic acid is a metabolite of serotonin produced by carcinoid tumours. It is detectable in the urine in metastatic disease.

False positives may occur with certain foods, for example bananas, avocado, aubergine, nuts and tomatoes, as well as various cough and cold preparations.  

2x24hr urinary metanephrines

Although phaeochromocytoma is not usually associated with MEN1, screening should be performed at the slightest suspicion, since it is a life threatening condition.

Urinary metanephrines are the most sensitive and specific, widely available screen for phaeochromocytoma. All patients with strongly positive results (>3x upper limit of normal) should be considered as having a phaeochromocytoma requiring immediate treatment and investigation.

Endoscopic ultrasound scan

This may aid visualisation of small pancreatic lesions.

Selective venous sampling of the pancreas

Selective venous sampling, together with calcium infusion to stimulate peptide secretion, may be performed to aid precise localisation and to define anatomy prior to pancreatic surgery.

Octreotide uptake scan

This may be performed to aid localisation of occult neuroendocrine tumours, as well as to visualise metastatic disease, though this is rarely necessary in MEN1.

Metaiodo-benzylguianidine scan

This may be performed to aid localisation of occult neuro-endocrine tumours, which do not take up octreotide, as well as to visualise metastatic disease. It is rarely necessary in MEN1.

Random recumbent renin and aldosterone

Adrenocortical tumours should be assessed for function using a baseline random renin and aldosterone ratio. Ratios above 800 should prompt medication review and formal evaluation for possible Conn's syndrome.

2x24hr urinary collections for urinary free cortisol

Adrenocortical tumours should be assessed for glucocorticoid secretion with urinary collections and a dexamethasone suppression test.

Low dose dexamethasone suppression test

If there is a high clinical suspicion of glucocorticoid excess or Cushing’s syndrome, proceed to a LDDST.