Insulinoma

Typical presentation of an insulinoma is a patient who has recognised that they need to eat frequently to prevent having a 'funny turn'.

Typically glycopaenic attacks will come on after a fast, on waking, or if a meal is skipped or eaten later than usual.

The patient may have noticed that eating more frequently prevents attacks and may have identified certain carbohydrate foods as aborting attacks most rapidly. Some people will have had severe episodes treated by strangers or paramedical staff, who have recognised the 'hypo' and assumed that the patient has diabetes.

Some patients will describe symptoms occurring after heavy meals, for example as a dip in concentration or energy one to two hours following consumption of a meal, rather than on fasting.

This is more suggestive of reactive hypoglycaemia though may still merit thorough assessment.

Hypoglycaemic attacks are usually (but not always) terminated quickly by food.

Epileptic attacks are often followed by severe headaches and tiredness.

Vasogenic or hypotensive epiosodes are usually terminated by lying prone and are usually followed by immediate resolution of all symptoms.

Cardiac arrhythmias will often have abrupt onset and offset, and some patients will have developed strategies to terminate them for example Valsalva manoeuvres, or lying or sitting quietly while waiting for them to settle.

Autonomic features of glycopaenia may be obvious. The attack may start with a feeling of hunger but quickly be described as more like a panic attack with anxiety, sweating, dizziness, tremulousness, pallor and palpitations.

These symptoms, if not clearly related to fasting, may raise the possibility of thyrotoxicosis or phaeochromocytoma.

Neuroglycopaenia may manifest itself in many ways. Typical 'funny turns' may not be experienced, and some patients present with altered behaviour, aggression, or a personality change.

Others may describe altered consciousness, transient neurological signs or fits, which may need to be investigated on their own merits. For this reason, rigorous neurological assessment for possible epilepsy or cerebrovascular disease will have been conducted before the diagnosis is considered.

Some patients will experience palpitations, altered consciousness and loss of consciousness. This raises the possibility of cardiac arrhythmia and may lead to cardiological assessment before the diagnosis is considered. If this has not occurred, ensure that the precise history surrounding the palpitations is documented, exclude other cardiac symptoms, and assess their exercise tolerance.

A full family history is also mandatory in case of familial cardiac disease, for example hypertrophic obstructive cardiomyopathy or Wolf Parkinson White syndrome, which might cause diagnostic confusion.

Menopausal flushes are typically associated with a feeling of heat and excessive sweating rather than pallor with hypoglycaemia.

Carcinoid flushes are often associated with diarrhoea, and sometimes with wheezing, though do not tend to be associated with sweating. Suggestive features should prompt assessment of urinary 5HIAAs to seek other neuroendocrine tumours.

Panic attacks with anxiety, sweating, hypertension or collapse are suggestive of phaeochromocytoma.

Weight gain typically occurs with insulinomas, whereas patients with reactive hypoglycaemia do not usually develop this.

Patients and relatives may have suspected diabetes, and many patients will have tested their fingerprick glucose prior to referral.

Blood glucose below 2.2mmol/l on a near patient test for example using a 'BM meter' is highly suggestive but not diagnostic of pathological hypoglycaemia.

Diarrhoea and steatorrhoea may occur in any pancreatic tumour, including insulinoma, although this is not typical.

Ask whether there any risk factors for other diseases which might mimic hypoglycaemia. For example head injuries or febrile convulsions increase the risk of epilepsy.

Constipation is typical with hypercalcaemia either due to parathyroid hormone related peptide (PTHrP) release, metastatic disease, or associated hyperparathyroidism in multiple endocrine neoplasia type 1.

Changes in bowel habit may accompany any gastrointestinal malignancy, including neuro-endocrine tumours, due to local effects. This warrants dedicated investigation, usually with direct endoscopic examination.

90% of insulinomas tend to be benign and 90% are also small, single and isolated. Malignant insulinomas do occur, however, and 10% insulinomas occur within a syndrome: multiple endocrine neoplasia type 1.

Other malignancies may secrete insulin like growth factor-II, which also presents with hypoglycaemia. Consider testing IGF-II levels in a patient with non factitious spontaneous hypoglycaemia associated with suppressed insulin.

Easy tanning and deepening of skin colour occur in Addison’s disease which may also present with dizziness, poor concentration and documented hypoglycaemia.

Facial angiofibromas, collagenomas and lipomas may be associated with MEN1.

Excessive thirst, nocturia, constipation, dyspepsia and nausea may be suggestive of hypercalcaemia and raise the possibility of MEN1.

Prolactinoma is the commonest functioning pituitary tumour in MEN1, so ask specifically about galactorrhoea, breast swelling, oligomenorrhoea, erectile dysfunction or loss of libido.

New headache or visual symptoms also require urgent evaluation.

Pituitary problems, hyperparathyroidism or other pancreatic, renal or other neuroendocrine tumours are highly suggestive of MEN1. This classically presents with pituitary, parathyroid and pancreatic disease, and approximately 10% of insulinomas occur within this syndrome.

Epilepsy may also be familial, as may some cardiological causes of episodic palpitations and collapse. Family history of sudden deaths or deaths by drowning should prompt a thorough cardiac assessment as well as investigation for possible familial phaeochromocytoma rather than insulinoma.

Multiple medications interfere with prolactin release. Multiple indigestion remedies contain calcium carbonate, and dietary supplements may also contain calcium and vitamin D which may lead to elevations in serum calcium.

Insulin or sulphonylureas also cause hypoglycaemia, and access to these agents, for example occupationally, or through a family member should raise the possibility of factitious hypoglycaemia.

Guar gum may be taken to prevent hypoglycaemia.

Apparently spontaneous hypoglycaemia sometimes occurs in people with diabetes or those with access to hypoglycaemic agents. Healthcare professionals and domestic carers of people with diabetes have access to both insulin and sulphonylureas which will cause severe hypoglycaemia which may be difficult to manage.