1. GENERAL INFORMATION
1.1 Incidence, risk factors and pathophysiology
Hypoglycemia is defined as a serum glucose level of <40 mg/dL. Hypoglycaemia specifically related to cancer is rare and is caused by several mechanisms:
• Production of insulin by islet-cell tumours (malignant insulinomas, which represent about 10% of all insulinomas).
• Production of insulin-like products or compounds with low molecular weight and non-suppressible insulin-like activity (e.g. insulin-like growth factor (IGF)-1, IGF-2, somatomedin A and somatomedin C) by large non-islet cell tumours, such as mesenchymal tumours (e.g. hemangiopericytomas, fibrosarcomas, leiomyomas, mesotheliomas, neurofibromas) as well as other tumour types (e.g. hepatomas, neuroblastomas).
• Excessive glucose consumption by large tumours that exceeds hepatic production.
• During end-stages of hepatic failure (as a consequence of decreased glycogenolysis and gluconeogenesis) or in pituitary failure (as a consequence of depressed secretion of counter-regulatory hormones such as adrenocorticotropic hormone (ACTH) and growth hormone).
• It may also be a complication of anti-cancer drug treatment (e.g. methotrexate or 6-mercaptopurine).
The most common cause of hypoglycaemia is medication (e.g. insulin, oral hypoglycaemic drugs, coumarin, salicylates, p-aminobenzoic acid, propoxyphene, haloperidol, stanozolol, ethanol, hypoglycin, carbamate insecticide, disopyramide, isoniazid, methanol, pentamidine, sulfonamide, tricyclic antidepressants, organophosphates, propranolol plus ethanol, didanosine, chlorpromazine, quinine, sulfa drugs, fluoxetine, sertraline, fenfluramine, trimethoprim, thiazide diuretics, thioglycolate, tremetol, ritodrine, disodium ethylenediaminetetraacetic acid (EDTA), clofibrate, angiotensin converting enzyme (ACE) inhibitors, and lithium.), but is might also be seen in severe infections, septic shock, hepatic or pituitary failure.
2.1 Clinical presentation
Symptoms may occur at glucose levels higher than 40 mg/dL depending on the rapidity of onset. Symptoms are worst in the early morning. Classic symptoms of hypoglycaemia include neurogenic symptoms (e.g. tremulousness, palpitations, anxiety, sweating, hunger and paresthesias) as the result of the perception of physiological changes caused by the autonomic response to hypoglycaemia followed by neuroglycopenic symptoms (e.g. confusion, sensation of warmth, weakness or fatigue, severe cognitive failure, seizure, coma).
The diagnosis of hypoglycemia is by serum glucose determination. The cause of hypoglycemia can be suggested by determination of plasma insulin and C-peptide concentration
• A plasma insulin concentration of 3 µU/mL when the plasma glucose concentration is below 55 mg/dL indicates an excess of insulin and is consistent with insulinoma. There is an overlap between normal subjects and patients with insulinoma
• Plasma C-peptide at the end of a fast distinguishes endogenous from exogenous hyperinsulinaemia. In patients in whom plasma glucose concentrations fall below 45 mg/dL (2.5 mmol/L), there is no overlap in the values in insulinoma patients (> 200 pmol/L or 0.6 ng/mL). and normal subjects.
In case of doubt a supervised 72-hour fast can be performed to differentiate between an insulinoma and non-islet cell tumours.
The prognosis depends on the primary tumour. Most often this symptom is a end-stage symptom with a bad prognosis. Delay in treatment can result in severe complications as coma, cardiac dysrhythmia, permanent neurological deficits or in death.
Mild hypoglycaemia may be managed by
• Increasing frequency of energy intake with frequent light meals and carbohydrate snacks, as astandard treatment option, on a type C basis.
• Administration of IV infusions of dextrose solutions, as a standard treatment option, on a type C basis.
Symptomatic hypoglycaemia may require
• Glucose IV infusions: administration 50 mL of 50% dextrose IV bolus followed by 10% glucose IV infusion in water by central venous line to avoid vein sclerosis. This option is suitable for individual clinical use , on a type C basis.
• Corticosteroids are suitable for individual clinical use, on a type C basis
• Glucagon (1 mg/dose IV or 0.06-0.3 mg/hour, delivered by a portable pump) produces a glucose increase in patients with insulinoma. However, because its insulin-releasing effect, it may also stimulate the insulinoma to release its insulin and subsequently cause hypoglycaemia. It acts on liver glycogen converting it to glucose. This option is to be considered as suitable for individual clinical use, on a type 3 level of evidence.
• Diazoxide (3-8 mg/kg/d PO divided q 8h) produces an increase in blood glucose within 1 h by inhibition of insulin release from the tumour. It is suitable for individual clinical use, on a type 3 level of evidence.
• Specific anti-cancer treatment is a standard treatment option, on a type C basis.
Dr. Dirk Schrijvers (Reviewer)
University Hospital Antwerp – Antwerp, Belgium
Dr. Silvia Spinazzé (Associate Editor)