Hypoglycaemia

Hypoglycaemia is an abnormally low level of glucose in the blood. Almost all cases of hypoglycaemia occur in people with Type 1 diabetes mellitus, in whom the pancreas fails to produce enough insulin, resulting in an abnormally high glucose level. To lower the level, insulin is given. Too high a dose of insulin can reduce the blood glucose to an excessively low level.

Hypoglycaemia can also occur if a diabetic person misses a meal or takes strenuous exercise. Less commonly, the condition may occur in people with Type 2 diabetes mellitus (in which body cells are resistant to the effects of insulin).

Rarely, the condition can result from drinking too much alcohol or from an insulin-producing pancreatic tumour. Symptoms include sweating, hunger, dizziness, trembling, headache, palpitations, confusion, and sometimes double vision. The person’s behaviour is often irrational and aggressive. Coma may occur in severe cases.

Hypoglycaemia may also be the cause of seizures and jittery behaviour in newborn babies (see neonatal hypoglycaemia). At the first sign of a hypoglycaemic attack, an affected person should consume a sugary food or drink. If the person has lost consciousness, emergency medical help is required; the patient must receive an injection of glucose solution or the hormone glucagon.

Reactive hypoglycaemia

Reactive hypoglycaemia is a form of hypoglycaemia (low blood glucose levels) that occurs within a few hours of eating foods that are rich in glucose. In reactive hypoglycaemia, the body overreacts to the sudden rise in blood sugar by releasing large amounts of insulin. This results in a rapid and excessive drop in the blood sugar level causing hypoglycaemic symptoms.

Hypoglycaemia in detail - technical

Essentials

Hypoglycaemia is defined as a blood glucose concentration below 3.0 mmol/litre, which is clinically important because of its effect on brain function. Much the commonest cause is excessive (in relation to intake of food and drink) administration of insulin or sulphonylurea drugs to patients known to have diabetes, but there are many rarer causes including insulinoma, toxins (alcohol), organ failure (hepatic), endocrine diseases (adrenal insufficiency, pituitary insufficiency), non-islet cell tumour hypoglycaemia, autoimmune insulin syndrome, factitious or felonious administration of insulin/sulphonylureas, and infections (malaria).

Clinical features—patients classically present either to the Emergency Department in a stuporose or comatose state with concurrent hypoglycaemia, or to outpatient services with a normal blood glucose level but a history suggesting recurrent neuroglycopenic episodes or progressive neurological/psychological dysfunction. Recognized clinical syndromes include: (1) acute neuroglycopenia—profuse sweating, anxiety/nervousness, tremor, tachycardia, hunger, and paraesthesiae, also speech and visual disturbances, unsteady gait and confusion; (2) subacute neuroglycopenia—reduction in spontaneous movements and speech, somnolence, inefficient cerebration, personality change, and amnesia of varying severity; (3) chronic neuroglycopenia—insidious changes in personality, defective memory, psychosis, or mental deterioration resembling dementia. The symptoms of acute and subacute neuroglycopenia are ephemeral but—unless aborted by restoration of normoglycaemia—can lead to stupor, coma or (in exceptional cases) death.

Diagnosis and management—hypoglycaemia is usually detected by point-of-care blood glucose determination and confirmed by formal laboratory blood glucose analysis. Treatment (in the patient unable to drink or eat safely) is with intravenous glucose 25 g (50 ml of 50% weight/volume) after (in cases where there is doubt as to the cause) blood has been withdrawn for subsequent laboratory analysis, most importantly for total insulin immunoreactivity, C-peptide, and proinsulin, and in some cases for alcohol, sulphonylureas and other assays. Glucagon 1 mg may be given intramuscularly if venous access is not available.

Particular causes of hypoglycaemia

Insulinoma—insulin-secreting β cell tumours are the most common endocrine neoplasm of the pancreas; most are benign and solitary, but about 10% are multiple (often as part of the MEN1 syndrome) and about 10% are malignant. Diagnosis is made by demonstrating that symptoms are caused by hypoglycaemia (typically provoked by fasting and/or rigorous exercise), relieved by intravenous glucose, and associated with inappropriately high plasma concentrations of total immunoreactive insulin, C-peptide, proinsulin, and proinsulin-like fragments with regard to the prevailing blood glucose concentration. No imaging technique is sufficiently reliable to justify dismissing a diagnosis made on sound clinical and biochemical grounds. The treatment of choice is surgical ablation. Localization by an experienced surgeon at laparotomy is remarkably (96%) successful, but can be further improved by use of intra-operative ultrasound.

Non-islet cell tumour hypoglycaemia—results from overproduction of an abnormally large form of IGF-2 or (rarely) IGF-1. Can occur with almost every histological type of malignant tumour, but least uncommonly with haemangiopericytomas, sarcomas, and primary hepatomas.

Autoimmune insulin syndrome—due to polyclonal autoantibodies to insulin that bind and sequester insulin secreted in response to a meal, and then release it after absorption is complete, producing an inappropriately high free plasma insulin level. Treatment is dietary and aimed at avoiding excessive insulin secretion in response to meals until spontaneous remission occurs, usually within a few years of onset.

Alcohol-induced hypoglycaemia—the most common cause of noniatrogenic hypoglycaemia, which typically develops within 6 to 36 h of the ingestion of moderate to large amount of alcohol (>30 g) by a fasting or malnourished subject.

Introduction

Hypoglycaemia means low blood glucose concentration (<3.0 mmol/litre). It is a biochemical abnormality whose importance lies in its effects upon brain function. These are responsible, directly or indirectly, for the signs and symptoms produced by hypoglycaemia and often provide the first clue to the presence of curable or preventable disease.

The brain obtains glucose from the blood by means of facilitated transport and mainly utilizes the glucose-transporting protein (GLUT1 or SLC2A1). The activity of this protein is increased by hypoglycaemia and reduced by hyperglycaemia. It is not insulin-dependent. Although blood glucose concentration is the single most important factor determining glucose availability to the brain, it is not the only one. Indeed there is a poor correlation between blood glucose concentration and the severity and nature of cerebral symptoms—especially in diabetic patients. It is therefore important to distinguish hypoglycaemia, a description of blood glucose, from neuroglycopenia, which is responsible for the signs and symptoms to which hypoglycaemia gives rise. Several distinct, but not mutually exclusive, neuroglycopenic syndromes are recognized.

Acute neuroglycopenia, the most common, is normally associated with iatrogenic and experimental hypoglycaemia and is characterized by profuse sweating, anxiety/nervousness, tremor, tachycardia, hunger, and paraesthesia—all of which can be attenuated by adrenergic and cholinergic blockade—and by speech and visual disturbances, unsteady gait, confusion, and a sense of fatigue, which are independent of the autonomic nervous system.

Subacute neuroglycopenia occurs in most varieties of spontaneous hypoglycaemia and, when it occurs in insulin-treated diabetic subjects, is called hypoglycaemia unawareness. It is characterized by a reduction in spontaneous movements and speech, somnolence, inefficient cerebration and work performance, personality change, and amnesia of varying severity. Other signs and symptoms common to acute and subacute neuroglycopenia include transient hemiplegia, hypo- or hyperthermia, convulsions, diplopia, and strabismus. The symptoms of acute and subacute neuroglycopenia are ephemeral but, unless aborted by restoration of normoglycaemia, can lead to stupor, coma, or, in exceptional cases, death from cerebral oedema.

Chronic neuroglycopenia is rare and virtually confined to patients with hypoglycaemia due to insulinoma or diabetic patients overzealously treated with insulin. It is characterized by insidious changes in personality, defective memory, psychosis—often with paranoid features—or mental deterioration resembling dementia. Temporary elevation of the blood glucose level has no discernible effect on cerebral or neuronal function but removal of the causative agent often does over the course of a few years.

Hyperinsulin neuronopathy, the clinical features of which may be mistaken for motor neuron disease, is a form of chronic neuroglycopenia.

Normoglycaemic neuroglycopenia, postulated to occur as an acquired abnormality in adults with diabetes and as a possible explanation for symptomatic reactive hypoglycaemia was identified as a hereditary disorder in siblings with deficiency of the glucose transporter GLUT1. In infants it produces neurological deficits characterized by infantile seizures, spacisticy, ataxia, and hypoglycorrhachia. In adults it produces an acute neuroglycopenic reaction to lower than usual, but still normoglycaemic, blood glucose concentrations in susceptible subjects.

Physiological considerations

There is a hierarchy in the activation of brain centres as hypoglycaemia develops which is, however, not often observed in spontaneous hypoglycaemia. The tissue most sensitive to a falling blood glucose level is the normal pancreatic β cell which virtually ceases secreting insulin as blood glucose concentrations fall to about 4.0 to 4.2 mmol/litre. The sympathetic nervous system is activated and glucagon is secreted as the blood glucose concentration reaches about 3.7 mmol/litre. Stimulation of growth hormone secretion occurs at glucose levels of about 3.5 mmol/litre and that of ACTH and cortisol at about 3.3 mmol/litre. The threshold for vasopressin release has not been determined. Most subjects experience symptoms only after their blood glucose concentration has fallen to less than 3 mmol/litre, but objective evidence of minor cognitive impairment, of which the subject is usually completely unaware, occurs at concentrations nearer to 4 mmol/litre.

Patients, whether diabetic or not, with recent experience of hypoglycaemia often tolerate lower blood glucose levels before symptoms develop and counter-regulatory hormones are secreted. They remain, however, just as sensitive to the deleterious effect of hypoglycaemia on cognitive function.

Some of the cerebral symptoms of neuroglycopenia and effects upon neuronal viability are due to the liberation of the excitatory amino acids glutamate and aspartate, rather than solely to decreased intracellular energy production.

Definition

Hypoglycaemia is defined arbitrarily by the blood glucose concentration; it is not determined by whether symptoms are present or not. For most purposes, an arterial (or capillary) blood glucose concentration of less than 3.0 mmol/litre can be considered diagnostic of hypoglycaemia and one of 2.5 mmol/litre or less pathological and demanding of investigation as to cause. The possibility that a patient’s symptoms are of neuroglycopenic origin should not be dismissed solely on the basis of blood glucose concentration. Normoglycaemic neuroglycopenia must be considered.

Classification

Iatrogenic hypoglycaemia as a consequence of insulin or sulphonylurea treatment for diabetes is common and accounts for most hypoglycaemia encountered in practice. It seldom presents diagnostic difficulties. There are, on the other hand some 100 or so causes of spontaneous hypoglycaemia, all of which are rare. Collectively, they are responsible for 0.1% of all patients arriving in emergency or medical investigation departments.

Table 1 lists the main causes of hypoglycaemia, which vary in frequency from country to country. Although all may occur in infants and children, the main causes of hypoglycaemia in this age group are not usually encountered in adults and not considered further in this article.

Table 1 Principal causes of hypoglycaemia
Induced  
Insulin: iatrogenic, accidental, factitious, felonious
Sulphonylurea: iatrogenic, accidental, factitious, felonious
Spontaneous
Pancreatic causes Insulinoma: benign, malignant, multiple, and microadenomatosis
Insular hyperplasia: hyperinsulinaemic hypoglycaemia or functional hyperinsulinism
Pluriglandular syndrome
Pancreatitis
Extrapancreatic IGF-2 and IGF-1 secreting neoplasms Mesenchymal tumours
Haemangiopericytoma
Primary hepatic carcinoma
Adrenal tumour
Various other carcinomas
Autoimmune hypoglycaemia Autoimmune insulin syndrome (AIS) and insulin-binding paraprotein secreting myelomas
Anti-insulin receptors
Pancreatic Graves’ disease
Toxic hypoglycaemia Alcohol
Drugs, e.g. pentamidine, quinine, paracetamol
Poisons, e.g. mushrooms
Alimentary (reactive) hypoglycaemia Postgastrectomy
Alcohol-provoked reactive hypoglycaemia
Noninsulinoma pancreatogenic hypoglycaemia
Idiopathic postprandial syndrome
Organ failure Septicaemia
Acute and chronic hepatocellular disease
Endstage kidney disease
Congestive cardiac failure
Acute respiratory failure
Endocrine disease Pituitary insufficiency: generalized or specific, e.g. selective ACTH deficiency
Adrenocortical insufficiency: congenital or acquired
Hypothyroidism
Selective hypothalamic insufficiency
Phaeochromocytoma
Inborn errors of metabolism Hepatic glycogen storage diseases
Hereditary fructose intolerance (HFI) and galactosaemia
Disorders leading to defective gluconeogenesis (e.g. fructose-1,6-bisphosphatase deficiency)
Disorders of mitochondrial β-oxidation (e.g. medium-chain acyl-CoA dehydrogenase deficiency, MCAD).
Hypoglycaemia of the newborn Transient hyperinsulinaemic hypoglycaemia
Persistent hyperinsulinaemic hypoglycaemia
Hypoinsulinaemic hypoglycaemia of the newborn
Miscellaneous causes Bacterial, viral, and parasitic infections, especially malaria
Diseases of the nervous system
Prolonged carbohydrate deprivation: starvation, anorexia nervosa
Excessive exercise (especially in combination with certain drugs)
Chronic renal dialysis

Presentation

Patients classically present either to emergency departments in a stuporose or comatose state with concurrent hypoglycaemia, or to outpatient departments with a normal blood glucose level but a history suggestive of recurrent neuroglycopenic episodes or progressive neurological/psychological dysfunction.

Management of the stuperose/comatose patient

Hypoglycaemia should be suspected in any case of altered consciousness, coma, hemiplegia, apparent alcoholic intoxication, or epilepsy, and eliminated or supported (though not established) by a point-of-care blood glucose determination. The diagnosis is confirmed by formal laboratory blood glucose analysis. Hypoglycaemia may also be caused by, and contribute to the symptomatology of, congestive cardiac failure, liver or kidney disease, malaria, and other severe infections. Management falls quite clearly into two separate phases.

Emergency treatment

Glucose 25 g (50 ml of 50% w/vol) should be given intravenously to alleviate hypoglycaemia after sufficient venous blood (20–30 ml) has been withdrawn for subsequent laboratory analysis to determine its cause. Glucagon 1 mg may be given intramuscularly if venous access is not available, especially in cases of iatrogenic hypoglycaemia (in which it is usually effective).

Recovery of consciousness ordinarily occurs within 10 min. A further injection of 25 g glucose plus 100 mg hydrocortisone is indicated if recovery is delayed beyond 20 min. Overtreatment with intravenous glucose must be avoided. Specific measures to reduce brain swelling should be introduced if recovery does not occur within a further 20 min.

Prolonged, formerly called irreversible, hypoglycaemic coma is due to cerebral oedema and a consequence of profound hypoglycaemia generally lasting 5 h or more. Its treatment includes the use of intravenous mannitol and dexamethasone. Blood glucose must be monitored constantly and sufficient glucose infused to keep it within the range of 5 to 10 mmol/litre until consciousness is restored or permanent brain damage is established. In cases of suicidal insulin or sulphonylurea overdose, glucose in doses up to 80 g/h given as a 25 to 50% solution through a central line may be required.

Investigation

The second and third stages are similar to those employed in investigating patients suspected of suffering from a hypoglycaemic disorder but who are currently asymptomatic.

Management of the asymptomatic patient suspected of having a hypoglycaemic disorder

Diagnosis takes place in three sequential stages:

  1. Suspicion of hypoglycaemia and its confirmation by measurement of the blood glucose concentration during a spontaneous neuroglycopenic episode
  2. Determination of its aetiology on the basis of specific investigative procedures
  3. Localization of the lesion responsible if the hypoglycaemia has an anatomico-pathological rather than a purely metabolic aetiology

Confirmation of hypoglycaemia

Most patients, except those presenting in a stupor or coma, are normoglycaemic and asymptomatic when first seen. Suspicion of hypoglycaemia is aroused by a history of subacute neuroglycopenia, e.g. episodes of altered behaviour or disturbed consciousness, or of symptoms suggestive of intermittent episodes of acute neuroglycopenia. Because amnesia is often a feature of their illness, patients may be unable to supply a reliable history.

Exclusion or confirmation that a patient’s symptoms are hypoglycaemic in origin can often be achieved by teaching them, or their relatives, to collect capillary blood during spontaneous symptomatic episodes occurring in the course of everyday life. Blood collected into specially prepared tubes or filter paper should be sent to the laboratory for glucose analysis since point-of-care monitoring systems are insufficiently reliable in the hypoglycaemic range to warrant initiation of detailed investigation and may cause confusion. A blood glucose concentration during a symptomatic episode greater than 3.5 mmol/litre effectively eliminates hypoglycaemia as its cause. Glucose concentrations lower than this are unusual and require further investigation.

Hyperinsulinism

This is a misnomer for the syndrome to which insulinoma and other β-cell abnormalities give rise. It would be better called dysinsulinism since its hallmark is inappropriate, rather than excessive, secretion of insulin or proinsulin.

Insulinoma

Insulin-secreting tumours (insulinomas) are the most common type of neoplasm affecting the endocrine tissues of the pancreas. They have an incidence of one case or more per million of the population. Eighty per cent of insulinomas are benign and solitary, 7 to 10% are multiple—often as part of multiple endocrine neoplasia type 1 (MEN1) syndrome—and 8 to 10% are malignant. They occur at any age but are rare before the age of 10 and infrequently diagnosed after the age of 70. The lack of cases after age 70 may be due to their mode of presentation, which is often that of progressive dementia, rather than to their rarity. There is a 6:4 ratio in favour of women for benign but not for malignant tumours.

Insulinomas are composed mainly, or exclusively, of β cells. Most are between 10 and 20 mm in diameter at diagnosis, though tumours as small as 5 mm in diameter have been associated with severe symptoms. Regardless of size, they occur at all sites in the pancreas with equal frequency.

Histological classifications, while valuable for the light they throw on insulin secretory mechanisms, contribute little to clinical management. Malignant insulin-secreting tumours are impossible to distinguish, clinically or histologically, from benign ones unless metastases are present. Some have the histological appearance of carcinoid tumours and both may contain and secrete other peptide hormones of which glucagon, somatostatin, ACTH, and GHRH are amongst the most common. Only rarely, however, do these biochemical endocrinopathies manifest themselves clinically. There is no evidence that malignant tumours ever begin as benign tumours or that benign tumours ever become malignant.

The average time between the onset of symptoms and diagnosis of insulinoma is currently about 1 year but symptoms persisting over 30 years or more without evidence of permanent brain damage are not unknown. Diagnostic delays are usually due to reluctance by patients to seek help or failure by clinicians to suspect hypoglycaemia, rather than any difficulties in confirming the presence of an insulinoma once the possibility has been considered. Only very rarely is an insulinoma found at autopsy as the cause of unexplained death.

In a minority, probably not exceeding 1 to 2%, functionally defective β cells are distributed throughout the pancreas rather than in discrete tumours. Clinically and biochemically, such patients are indistinguishable from patients with insulinomas. Biologically, such patients resemble infants with persistent hyperinsulinaemic hypoglycaemia of infants (formerly nesidioblastosis).

Chemical pathology

Endogenous hyperinsulinism is characterized by the failure of the abnormal β cells to stop secreting insulin in response to hypoglycaemia. This is ordinarily the most sensitive physiological response to a falling blood glucose concentration and becomes apparent at a level (4.2–4.0 mmol/litre) well above the threshold for neuroglycopenic symptoms. A consequence of insulin secretion persisting during fasting is inhibition of hepatic glucose release and a gradual fall in blood glucose to below the level capable of sustaining normal brain function.

Paradoxically, the functionally abnormal β cells are often insensitive to hyperglycaemia per se and so produce glucose intolerance as well as fasting hypoglycaemia. They do, however, respond, often excessively, to other insulin secretagogues including glucagon, sulphonylureas, L-leucine, and the intestinal incretins gastric inhibitory polypeptide and glucagon-like peptide-1, and may therefore present with reactive rather than fasting hypoglycaemia.

Typically, plasma cortisol and growth hormone levels in patients with insulinomas are normal even in the presence of hypoglycaemia. This would ordinarily be considered evidence of hypothalamic–pituitary insufficiency but responsiveness returns after restoration of permanent normoglycaemia. Plasma free fatty acid and β-hydroxybutyrate concentrations are typically suppressed (<600 µmol/litre) but rise, though not to expected levels, during prolonged fasting.

Diagnosis

Diagnosis is made by demonstrating that the symptoms are caused by hypoglycaemia, provoked by fasting and/or rigorous exercise, relieved by intravenous glucose, and are caused by inappropriate insulin and/or proinsulin secretion. Plasma concentrations of total immunoreactive insulin, C-peptide, proinsulin, and proinsulin-like fragments are all inappropriately high having regard to the prevailing blood glucose concentration but are not necessarily high in absolute (quantitative) terms.

Thus, in the presence of concurrent hypoglycaemia (blood glucose <3 mmol/litre), plasma total immunoreactive insulin concentrations of more than 30 pmol/litre and C-peptide concentrations of more than 100 pmol/litre are inappropriately high. When both peptide levels are inappropriately high, a diagnosis of endogenous hyperinsulinism is virtually certain, providing sulphonylurea ingestion and various rare autoimmune diseases and infections, such as malaria, can be excluded. If the patient was normo- or hyperglycaemic at the time of plasma sampling, the results of insulin, C-peptide, and proinsulin assays are uninterpretable.

Fasting combined with modest exercise under close observation for up to 48 h produces symptomatic hypoglycaemia with inappropriate hyperinsulinaemia (proinsulinaemia and C-peptidaemia) in over 95% of insulinoma patients but not in healthy men and women who, if they do become hypoglycaemic, do not experience symptoms or have inappropriately high plasma insulin levels. As an alternative to prolonged fasting, the overnight fasted patient can be exercised to exhaustion on a treadmill. In insulinoma patients, this fails to produce the normal suppression of plasma insulin and C-peptide secretion. It is, however, rarely necessary to subject a patients to these tests, especially if investigations are restricted to those who have blood glucose levels of less than 3 mmol/litre during spontaneous episodes occurring in everyday life. Dynamic function tests including oral glucose, tolbutamide, glucagon, L-leucine, and insulin–hypoglycaemia/C-peptide suppression tests are unnecessary for the diagnosis of hyperinsulinism.

Some 5 to 10% of insulinomas secrete only, or mainly, proinsulin and thus the diagnosis may be missed if an insulin-specific assay, rather than one capable of detecting total immunoreactive insulin, is used. Moreover, unusually efficient extraction of insulin by the liver can lead to low plasma total immunoreactive insulin concentrations in peripheral blood in the presence of genuinely inappropriate insulin secretion. This can occur in infants with hyperinsulinaemic hypoglycaemia as well as in adults with endogenous hyperinsulinism in whom inappropriately high plasma C-peptide levels will confirm the diagnosis. Hyperproinsulinaemia, e.g. a plasma proinsulin concentration greater than 20 pmol/litre, is found in some 95% of patients with endogenous hyper-insulinism; its absence should raise doubts about the accuracy of the diagnosis.

Pre- and intraoperative localization

A diagnosis of endogenous hyperinsulinism, established on the basis of inappropriate hyperinsulinaemia, is almost synonymous with one of insulinoma. The treatment of choice is surgical ablation. Localization by an experienced surgeon at laparotomy is remarkably successful (96%), but can be further improved by use of intraoperative ultrasound.

Though virtually every imaging technique has been advocated for preoperative localization of insulinoma, none is sufficiently reliable to justify dismissing a diagnosis made on sound clinical and biochemical grounds. Endoscopic ultrasonography, with a 90% prediction rate, and pancreatic intra-arterial calcium injection with hepatic venous sampling are currently the only imaging techniques that are useful for localization prior to operation. Hepatic venous sampling is especially indicated when surgery has failed to reveal a tumour and/or diffuse islet hyperplasia is suspected. It is the only way of establishing a diagnosis of noninsulinoma pancreatogenic hypoglycaemia preoperatively, which should never be made until sulphonylurea-induced hypoglycaemia has been demonstrably excluded.

Treatment

Surgical ablation ensures an excellent prognosis with no reduction in life expectancy except when the tumour is malignant. Even then, since these tumours grow slowly and rarely spread beyond the liver, removal of the primary tumour, and as many hepatic secondaries as possible, may add years of useful life. Operative mortality for adenomas is under 2%, except in older people. Benign tumours recur in up to 5% of patients.

In patients over 70 years of age, and others in whom surgery is impracticable, treatment with diazoxide (200–600 mg/day) combined with chlorothiazide (1 g/day) to increase its effectiveness, is well tolerated. It is the treatment of choice in hyperinsulinism due to diffuse islet hyperplasia, noninsulinoma pancreatogenic hypoglycaemia, and after surgical debulking in cases of metastatic insulinoma. Only when diazoxide/chlorothiazide treatment fails to relieve hypoglycaemia are other drugs, such as octreotide, β-blockers, or calcium channel blockers worth trying. In patients with malignant insulinomas, embolization or surgical debulking of hepatic metastases may produce remissions lasting several years—as may treatment with cytotoxic agents such as streptozotocin and 5-fluorouracil.

Non-islet-cell tumour hypoglycaemia

The symptoms of hypoglycaemia produced by non-islet cell tumours (NICTH) may be indistinguishable from that of insulinoma. The symptoms are almost invariably those of subacute neuroglycopenia and the features of autonomic nervous activation are absent. Biochemically, NICTH is characterized by fasting hypoglycaemia, hypoketonaemia, and low plasma total immunoreactive insulin, C-peptide, and proinsulin levels. Growth hormone, ACTH, and glucagon secretion are depressed during both hypo- and normoglycaemia and plasma levels of insulin-like growth factor 1 (IGF-1) are always low—unlike in insulinoma when they are normal or high.

NICTH can occur with almost every histological type of malignant tumour but is rare. Although sarcomas are disproportionately well represented, less than 1% of them develop hypoglycaemia. It is, however, common in patients with haemangiopericytomas, which are themselves rare. Amongst the carcinomas, no histological type is exempt from NICTH but only in primary hepatomas is it at all common.

Chemical pathology

Regardless of histological type, hypoglycaemia due to non-islet cell tumours (NICTH) results from overproduction of an abnormally large form of IGF-2 or, exceptionally, IGF-1.

‘Big IGF-2’ is generated by the removal of a 24 amino acid leader sequence from the N-terminal of prepro-IGF-2. Normally, it then undergoes cleavage at its C-terminal to produce regular IGF-2. Failure to do so leaves the E domain intact and leads to the appearance of big IGF-2 in the blood.

There is characteristically a marked reduction in the most plentiful of the plasma binding proteins, IGFBP3, and a partial compensatory increase in IGFBP2 the net effect of which is, however, to reduce IGF protein binding capacity. Consequently, plasma free (big) IGF-2 is increased without a corresponding increase in total immunoreactive IGF-2 which is often normal.

The exact mechanism by which big IGF-2 produces hypoglycaemia is unknown and may involve several steps, the most important of which is activation of insulin and IGF receptors on peripheral tissues and their increased uptake of glucose. The next most important step is the suppression of glucagon and growth hormone secretion resulting in reduced release of glucose by the liver.

Ectopic insulin secretion

Ectopic insulinomas are confined to the duodenum and are rare (<1%). Insulin production by non-islet cell tumours is even rarer, but does occur. The coincidence of an insulinoma and another type of tumour is more common.

Diagnosis

The diagnosis of NICTH is seldom in doubt once thorough investigations into the cause of hypoglycaemia have been initiated because:

  • hypoglycaemia, once it has developed, seldom remits for more than very brief periods after meals
  • the tumours are usually, though not invariably, sufficiently large to reveal themselves either on physical examination or as a result of comparatively straightforward imaging

In the laboratory, findings of low plasma insulin, C-peptide, and proinsulin concentrations (<30, <100, and <20 pmol/litre respectively) in the presence of hypoglycaemia and hypoketonaemia are highly suggestive of NICTH. Clinical laboratory assays that typically measure total IGF-2 are often reported as normal (50–100 nmol/litre) or high whereas IGF-1 levels are invariably low (<10 nmol/litre) except in IGF-1 secreting tumours. Consequently, plasma IGF-2:IGF-1 ratios, expressed on a molar basis, are abnormally high (>10) and not seen in any other condition except gross undernutrition and rare IGF-1 secreting tumours. Assays for the E domain of proIGF-2 have been developed. Although useful for establishing recurrence, they provide less accurate initial diagnostic information than the IGF-2:IGF-1 ratio.

The treatment of choice is surgical. In rare cases of benign tumour NICTH, the cure is permanent. In malignant cases, ablation or debulking of secondaries may produce prolonged remissions. Prednisolone, in doses up to 60 mg/day, produces improvement in the biochemical profile and remissions from hypoglycaemia in many cases, but has no effect upon tumour growth itself. Growth hormone and long-acting glucagon preparations also produce symptomatic relief given alone or with prednisolone. Benefit from diazoxide with chlorothiazide is less predictably than with insulinomas.

Postprandial syndrome

The appearance of symptoms suggestive of acute neuroglycopenia in relation to the ingestion of food has been called the postprandial syndrome. It has many causes, one of the less common being hypoglycaemia.

Reactive hypoglycaemia

Following an initial rise, venous blood glucose concentrations may decrease in normal healthy volunteers as far as 2 mmol/litre below fasting levels after ingestion of a liquid glucose load of 75 g or more on an empty stomach. A smaller fall in arterial blood glucose also occurs and may, in up to 50% of normal healthy subjects, be accompanied by mild symptoms. This phenomenon, referred to as reactive hypoglycaemia, rarely occurs in everyday life when normal mixed meals are eaten. When it does, diagnostic difficulties may arise since symptoms are usually vague, unspecific, and indistinguishable from those due to other illnesses, especially neurosis.

In the mid 20th century, the diagnosis of reactive hypoglycaemia, referred to by lay writers simply as hypoglycaemia, reached epidemic proportions in the United States of America. In most cases, the diagnosis was based on misattribution of a normal response to oral glucose to an illness. While some patients with postprandial syndrome may have a lower threshold to neuroglycopenia, experiencing symptoms at (arterial) blood glucose levels of 3.5 to 4.0 mmol/litre rather than the more customary level of 2.8 to 3.3 mmol/litre, most do not. Nor do they manifest any abnormalities of glucose homeostasis.

The criteria for the recognition and diagnosis of reactive hypoglycaemia were laid down at the Third International Symposium on Hypoglycaemia, adherence to which has greatly reduced the number of persons misdiagnosed. The criteria include a history of food-stimulated autonomic symptoms appropriate to acute neuroglycopenia—a capillary blood glucose concentration measured during a spontaneous symptomatic episode below 3 mmol/litre and rapid relief by oral glucose. Sometimes, when suspicion is high and blood collection during everyday life proves difficult, it may be necessary to give the patient a standard meal and observe the glycaemic, symptomatic, and electroencephalographic responses over the ensuing 5 h. The oral glucose load test is not appropriate.

The term ‘reactive hypoglycaemia’ is not a definitive diagnosis; it is only the first step towards determining causation. Almost every condition in which hypoglycaemia is induced by fasting may present as reactive hypoglycaemia. Therefore, organic causes, including acquired and inherited metabolic derangements, must be eliminated before making a diagnosis of idiopathic reactive hypoglycaemia—which is rare. Conditions in which patients experience only reactive, but not fasting, hypoglycaemia include partial gastrectomy and jejuno-oesophageal anastamosis (also referred to as alimentary hypoglycaemia) and, recently identified, noninsulinoma pancreatogenous hypoglycaemia. Reactive hypoglycaemia, unaccompanied by fasting hypoglycaemia, occurs in up to 2% of patients harbouring insulinomas. Autoimmune insulin syndrome usually produces only a reactive hypoglycaemia, but rarely develops sufficiently long after eating to be mistaken for fasting hypoglycaemia. Prolonged fasting does not, however, reproduce it.

Clinical features

Typically, patients present with a history of transient episodes of dizziness, anxiety, palpitations, sweating, hot flushes, and even convulsions or brief periods of altered consciousness, and extending over a period of 1 to 30 years. Between episodes they are asymptomatic but rarely in robust health. They rarely notice any relationship of symptoms to food but may do so when prompted. Physical, including radiological, investigation is generally normal except in alimentary hypoglycaemia. In them, but few others, food-induced reactive hypoglycaemia may be of sufficient severity as to cause loss of consciousness.

Acute neuroglycopenia-like symptoms experienced by patients with the postprandial syndrome are rarely associated with any abnormality of glucose homeostasis or insulin secretion though exaggerated enteroglucagon, gastric inhibitory polypeptide, and glucagon-like peptide-1 amide response to food may occur. Some patients are unduly sensitive to modest reductions in blood glucose concentration to which most healthy subjects would be oblivious and in them the possibility of nonhypoglycaemic neuroglycopenia may be entertained.

Alcohol-induced reactive hypoglycaemia

Symptomatic reactive hypoglycaemia may occur in healthy young subjects after ingesting a mixture of alcohol, sucrose, and quinine given as gin and tonic and, less commonly, with other mixtures of alcohol and carbohydrate on an empty stomach. Simultaneous ingestion of carbohydrate-rich snacks increases the severity of the hypoglycaemia; snacks rich in fat reduce it.

Diagnosis

Diagnosis of reactive hypoglycaemia is suggested by the clinical history and confirmed or refuted by glucose measurements made on capillary blood collected during spontaneous symptomatic episodes. Other laboratory tests, including measurement of plasma insulin, C-peptide, proinsulin, and β-hydroxybutyrate are used to exclude conditions such as noninsulinoma pancreatogenous hypoglycaemia, autoimmune insulin syndrome, and other conditions that do not produce hypoglycaemia during fasting but do require specific treatment.

Capillary blood glucose concentrations of less than 3.5 mmol/litre, measured in an accredited laboratory on two or more occasions, establish hypoglycaemia as a factor in the symptomatology. The oral glucose load test, formerly the linchpin for diagnosis, may be misleading especially when conducted on individuals who have taken a self-prescribed low carbohydrate diet (<100 g/day) and should rarely be employed. A standard glucidic breakfast providing 100 g of readily assimilated starchy food has been advocated in its stead but is seldom indicated.

Treatment

Prevention of fluctuations in blood glucose is key to the management of reactive hypoglycaemia and is achieved by minimizing the intake of rapidly absorbed carbohydrates such as sucrose, bread, and potato starch. Frequent small meals, rich in dietary fibre—and taken without alcohol—offer the best chance of symptomatic relief. Incorporation of soluble dietary fibre supplements, such as guar and glucomannan, in meals and taking α-glucosidase inhibitors, such as acarbose and miglitol, with them reduce blood glucose excursions but their side effects are often worse than the discomfort from minimal hypoglycaemia.

Prognosis

Idiopathic postprandial syndrome is a self-limiting disorder but may be resistant to all physical treatments. Some patients respond well to psychotherapy and/or avoidance of alcohol.

Autoimmune hypoglycaemia

Autoimmune diseases are important causes of spontaneous hypoglycaemia. Three main types are recognized.

Autoimmune insulin syndrome

The autoimmune insulin syndrome occurs throughout the world, especially in East Asia, but is increasingly recognized in the West. It is due to polyclonal autoantibodies to insulin resembling those produced in response to exogenous insulin but more likely to bind proinsulin and its cleavage products including C-peptide.

Hypoglycaemia typically occurs as a late response to the ingestion of food. Insulin secreted early in response to a meal is sequestered by antibodies present in the plasma and rendered temporarily inactive. Dissociation of the insulin–antibody complex, after absorption is complete, produces an inappropriately high free plasma insulin level resulting in hypoglycaemia. This, though often profound, is of limited duration, rarely leading to coma and never to death.

There is often a history of autoimmune disease affecting other organs, especially the thyroid, and many patients have received treatment with methimazole, carbimazole, or other thiol-containing drugs.

Free plasma insulin concentrations are always inappropriately high and C-peptide is usually depressed during hypoglycaemia. C-peptide concentrations may, however, be normal or high depending on the binding characteristics of the autoantibody.

Treatment is dietary and aimed at avoiding excessive insulin secretion in response to meals until spontaneous remission occurs, usually within a few years of onset. Surgery, in the mistaken belief that the patient has islet hyperplasia or insulinoma, must be avoided. Myelomas associated with IgG or IgA insulin binding paraproteins may be confused with autoimmune insulin syndrome. Treatment is supportive and of the primary disorder.

Insulin receptor autoantibodies

Hypoglycaemia due to insulin receptor autoantibodies is rare but may be the first indication of the causative disease. More often it develops in a patient already known to be suffering from an autoimmune disease or a neoplasm—especially lymphoma. Typically, hypoglycaemia is intractable but occasionally occurs only in response to food. Its immediate cause is binding of stimulatory autoantibodies to insulin receptors on hepatic and peripheral cell membranes, simulating the effects of insulin itself.

Clinically, the symptoms are indistinguishable from that of insulinoma though usually of shorter duration and greater severity. Plasma C-peptide and proinsulin concentrations are low (<20 pmol/litre). Plasma insulin, though also often low, may be very high (>1000 pmol/litre) due to its delayed clearance from the blood. Diagnosis can usually be inferred from the clinical associations and evidence suggestive of hyperinsulinism, e.g. coincident low blood glucose and β-hydroxybutyrate, but depressed plasma C-peptide, proinsulin (and usually insulin) concentrations rule it out. Definite diagnosis depends upon demonstrating antireceptor antibodies in the patient’s plasma using in vitro bioassay techniques.

Treatment is that of the primary disease. Glucocorticoids and other immunosuppressants have been used with benefit in some cases but although remissions may occur, the prognosis is generally poor.

Islet-cell stimulating antibodies

Antibodies capable of stimulating insulin release from isolated pancreatic β cells in vitro have been held responsible for a form of hyperinsulinaemic hypoglycaemia analogous to Graves’ disease of the thyroid. The evidence is, however, inconclusive and few documented cases have been published.

Drug and toxin-induced hypoglycaemia

Medicines and toxins, such as alcohol, paracetamol, quinine, amanita (fungi), and Blighia sapida (ackee) are collectively amongst the most frequent causes of noniatrogenic hypoglycaemia. They produce their effects in various ways, mostly by interfering with hepatic glucose production, counter-regulatory hormone action, or by stimulating insulin secretion.

Alcohol-induced hypoglycaemia

Alcohol-induced hypoglycaemia is the most common cause of noniatrogenic hypoglycaemia. The patient is usually stuporose or comatose. Sometimes they are aggressively uncooperative and their symptoms are attributed to alcoholic intoxication rather than to hypoglycaemia. Characteristically, hypoglycaemia develops within 6 to 36 h of the ingestion of moderate to large amounts of alcohol (>30 g) by fasting or malnourished subjects who may be, but often are not, habituated to alcohol. Hypothermia is more common than with other causes of hypoglycaemia and may provide the first clue to diagnosis. Children, in whom there is a 25% mortality rate, are particularly susceptible to this type of hypoglycaemia.

Blood glucose is less than 2.5 mmol/litre and alcohol is almost always present, generally at a concentration of less than 20 mmol/litre (100 mg/100 ml). Plasma and urinary ketones are high but often overlooked because traditional tests for ketones detect only acetone and acetoacetate rather than β-hydroxybutyrate—the redox pair member normally present in alcoholic ketoacidosis.

Once considered, the diagnosis is seldom in doubt and is due to the inhibition by alcohol of hepatic gluconeogenesis from lactate and glycerol. It can be confirmed by demonstrating hypoglycaemia, raised plasma β-hydroxybutyrate, and low plasma insulin, C-peptide, and proinsulin levels together with, in most cases, measurable amounts of alcohol.

Consciousness can be restored with intravenous glucose but not with glucagon, which is ineffective. Long-term treatment is avoidance of the predisposing factors.

Accidental, factitious and felonious hypoglycaemia

In these states, although hypoglycaemia is due to exogenous hypoglycaemic agents, this fact is not revealed by the history. The correct diagnosis emerges only from critical examination of laboratory test results and other nonclinical or forensic evidence. Typically, the patient is hypoglycaemic and stuporose or comatose when first seen and—unless the possibility of drug-induced hypoglycaemia is suspected from the outset, and appropriate samples of blood and urine collected for insulin, C-peptide, proinsulin, and sulphonylurea assay—the correct diagnosis may never be made.

Sulphonylureas

Dispensing or prescription errors are an important cause of hypoglycaemia—a sulphonylurea being substituted for another drug with a similar name—e.g. Diabinese (chlorpropamide) for Diamox (acetazolamide). In hospital, victims of accidental hypoglycaemia often have received medication intended for someone else. Because patients are usually older people and slip slowly into hypoglycaemic coma without warning, the diagnosis may be delayed or missed completely.

Deliberate sulphonylurea overdose with suicidal or murderous intent is uncommon. It may be difficult to distinguish from accidental overdose in a diabetic patient unless the plasma sulphonylurea level is grossly abnormal or a suicide note is found. Treatment with diazoxide or octreotide and intravenous glucose may be required for many days to prevent recurrent hypoglycaemia.

Insulin

Factitious insulin-induced hypoglycaemia is as common in previously healthy subjects as in insulin-dependent diabetics and is due to deliberate, but concealed, injection of insulin. The history suggests insulinoma but is eliminated by the laboratory results which reveal high plasma insulin and low C-peptide (and proinsulin) concentrations during hypoglycaemia. In long-standing factitious hypoglycaemia, and in insulin-treated diabetics, insulin antibodies may be present in the plasma. Although once considered a strong pointer to factitious hypoglycaemia, the presence of insulin antibodies should nowadays suggest autoimmune insulin syndrome.

Suicidal overdosing with insulin is not confined to diabetic patients and is usually unsuccessful. Most patients are found within 12 h of injecting themselves and are restored to consciousness by appropriate treatment. Plasma C-peptide is unrecordably low and (free) insulin concentrations generally greater than 2000 pmol/litre. In factitious hypoglycaemia, plasma insulin concentrations are generally lower than this.

Murder or attempted murder with insulin is rare and virtually confined to infants, critically ill patients, and older people. The victims are often dead when first seen; if suspected, the diagnosis can be made retrospectively by demonstrating inordinately high concentrations of insulin in blood drawn from a peripheral blood vessel or in tissue removed from the putative injection site. Blood, cerebrospinal fluid, and vitreous glucose measurements are uninterpretable after death.

Organ failure

Hypoglycaemia can occur, sometimes as a dominant feature, in almost any serious and life threatening illness. Most notably are: congestive cardiac failure; acute liver failure; chronic renal failure; bacterial, viral, and parasitic infections (especially malarial); and terminal malnutrition. The cause of the hypoglycaemia is seldom in doubt but its recognition and the restoration of normoglycaemia sometimes dramatically alter the course of the illness.

Endocrine hypoglycaemia

Hypoglycaemia is a rare but important presenting sign of several endocrine disorders of which Addison’s disease, panhypopituitarism, and isolated ACTH deficiency are the most common. The typical clinical features of endocrinopathy are inconspicuous and the diagnosis may be missed unless specifically sought through appropriate laboratory testing. Paradoxically, reactive hypoglycaemia is a rare manifestation of pheochromocytoma with which its symptomatology may be confused. Primary glucagon deficiency has only once been documented as a cause of hypoglycaemia.

Inborn errors of metabolism

Many inborn errors of carbohydrate metabolism—which usually present as hypoglycaemia in childhood—can first manifest themselves in adult life. Mild variants may be responsible for obscure cases of hypoglycaemia which occur only under very stressful conditions, such as prolonged fasting or exceptionally violent exercise, and for which no endocrine or organic cause can be found. Hereditary fructose intolerance causes hypoglycaemia as a dominant feature of the metabolic disturbance that characterizes the manifestations of this inborn error which are rapidly induced by consuming fruit, nuts, confectionery and meals containing fructose, sucrose and the related sugar alcohol, sorbitol. This condition is often undetected in infancy and many present for the first time with florid symptoms in adult life.

Further reading

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Bolli GB, Fanelli CG (1999). Physiology of glucose counterregulation to hypoglycemia. Endocrinol Metab Clin North Am, 28, 467–93.

Clark PM (1999). Assays for insulin, proinsulin(s) and C-peptide. Ann Clin Biochem, 36, 541–64.

Cryer PE (1999). Symptoms of hypoglycemia, thresholds for their occurrence, and hypoglycemia unawareness. Endocrinol Metab Clin North Am, 28, 495–500.

Cryer P E, et al. (2009). Evaluation and management of sdult hypoglycemic disorders: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab, 94, 709–28. 

Cryer P (2007). Hypoglycemia, functional brain failure, and brain death. J Clin Invest, 117, 868–70.

Grant CS (1999). Surgical aspects of hyperinsulinemic hypoglycemia. Endocrinol Metab Clin North Am, 28, 533–54.

Halsall DJ, et al. (2007). Hypoglycemia due to an insulin binding antibody in a patient with an IgA-κ myeloma. J Clin Endocrinol Metab, 92, 2013–16.

Kar P, et al. (2006). Insulinomas may present with normoglycaemia after prolonged fasting but glucose-stimulated hypoglycemia. J Clin Endocrinol Metab, 91, 4733–36.

Koch CA, Rother KI, Roth J (1999). Tumor hypoglycemia linked to IGF-II. In: Rosenfeld R, Roberts C Jr (eds) Contemporary endocrinology: the IGF system, pp. 675–98. Humana Press, Totowa, New Jersey.

Kwong PYP, Teale JD (2002). Screening for sulphonylureas in the investigation of hypoglycaemia. J R Soc Med, 95, 381–385.

Lteif AN, Schwenk WF (1999). Hypoglycemia in infants and children. Endocrinol Metab Clin North Am, 28, 619–46.

Marks V, Richmond C (2007). Insulin Murders; true-life cases. RSM Press, London. Marks V, Teale JD (1998). Tumours producing hypoglycaemia. Endocr Relat Cancer, 5, 111–29.

Marks V, Teale JD (1999). Drug-induced hypoglycemia. Endocrinol Metab Clin North Am, 28, 555–77. 

Marks V, Teale JD (1999). Hypoglycemia: factitious and felonious. Endocrinol Metab Clin North Am, 28, 579–601.

Nauck M, et al. (2007). Hypoglycemia due to paraneoplastic secretion of Insulin-Like Growth Factor-I in a patient with metastasizing large-cell carcinoma of the lung. J Clin Endocrinol Metab, 92, 1600–1605.

Seckle MJ, et al. (1999). Hypoglycemia due to an insulin-secreting small-cell carcinoma of the cervix. N Engl J Med, 341, 733–6.

Teale JD, Wark G (2004). The effectiveness of different treatment options for non-islet cell tumour hypoglycaemia. Clin Endocrinol (Oxf), 60, 457–60.

Vezzosi D, et al. (2007). Insulin, C-peptide and proinsulin for the biochemical diagnosis of hypoglycaemia related to endogenous hyperinsulinism Europ J Endocrinol, 157, 75–83. 

Wang D, et al. (2004). GLUT-1 deficiency syndrome: clinical, genetic, and therapeutic aspects. Ann Neurol, 57, 111–118.

Won JGS, et al. (2006). Clinical features and morphological characterization of 10 patients with non-insulinoma pancreatogenous hypoglycemia syndrome (NNIPHS). Clin Endocrinol (Oxf), 65, 566–78.