Non-Diabetic Hypoglycemia

Etiology

There are many causes of non-diabetic hypoglycemia. Hypoglycemia can be broadly divided into two main groups:

1. Insulin-mediated (hyperinsulinism)
2. Independent of insulin

Insulin-mediated (hyperinsulinism): The endogenous cause of hypoglycemia due to hyperinsulinism in a non-diabetic adult is secondary to Insulinoma and islet cell hyperplasia (nesidioblastosis).[1][2] Iatrogenic hyperinsulinism involves exogenous insulin intake or insulin secretagogues (sulphonylureas and glinides).[3]

Independent of insulin: Insulin independent hypoglycemia includes alcohol, visceral failure (liver/renal failure), critical illness, primary adrenal failure, anterior pituitary failure, severe sepsis, cerebral malaria, anorexia nervosa, glycogen storage disease, post-bariatric surgery, mesenchymal tumors with elevated IGF-2 levels, autoimmune hypoglycemia secondary to anti-insulin or anti-insulin receptor antibodies and drugs. Hypoglycemia caused by drugs is very common. Many drugs other than anti-hyperglycemic medications and alcohol have been reported. Common medications include quinolones, anti-malarial, glucagon, lithium, angiotensin-converting enzyme inhibitors, angiotensin receptor antagonists, non-selective B-blockers, etc.).[1]

In children, hypoglycemia is mainly secondary to IEM. It includes glycogen storage disease, fatty acid oxidation defect, ketogenesis defects, and gluconeogenesis disorders. Galactosaemia and hereditary fructose intolerance are rare genetic disorders associated with the body’s impaired ability to metabolize galactose and fructose, respectively.[4][5] ABCC8, KCNJ11, GLUD1, GCK, HADH, UCP2, HNF1A, HNF4A, SLCA16A1, HK1, PGM1, PMM2 mutations can result in congenital hyperinsulinism, with KCNJ11 and ABCC8 mutations accounting for 40% to 50% of all cases.[6]

Epidemiology

Non-diabetic hypoglycemia is relatively uncommon as compared to hypoglycemia in patients with diabetes. A large retrospective review of 38,898 patients admitted to hospitals with non-critical illness showed the estimated frequency of 36 per 10000 admissions.[7] It was noted that patients with age above 65 years on admission were 50% more likely to have an episode of hypoglycemia.[7]

The incidence of Insulinoma is estimated to be 0.4 per 100,000 person-years with 59% female preponderance and age of 47 years at the surgery.[8] Hypoglycemia is a well-known complication of bariatric surgery, especially Roux-en-Y gastric bypass.[9] A population-based study noted a 2 to 7 fold increase in hospital admission due to hypoglycemia in patients who underwent bariatric surgery. However, the absolute risk of hospitalization is very low (approximately 0.2%) with hypoglycemia after gastric bypass surgery. In comparison, the general population risk was 0.04%.[10] 

Another study noted that less than 1% of the patient after Roux-en-Y gastric bypass might require hospitalization due to hypoglycemia. Furthermore, less than 10% of patients may develop clinically significant hypoglycemia.[11] In a study involving 40 patients who had undergone Roux-en-Y gastric bypass, 75% of patients were noted to have asymptomatic hypoglycemia on continuous glucose monitoring.[12]

Pathophysiology

There are several characteristic symptoms of hypoglycemia. Initial symptoms would be varied and non-specific. There is the activation of the autonomic nervous system leading to both adrenergic and cholinergic responses. Adrenergic symptoms include pallor, tremors, anxiety, and arterial hypertension. Anxiety and arterial hypertension are secondary to catecholamine release. Increased glucagon secretion leads to increased glucose production. The cholinergic response predominantly involves sweating, hunger, and paraesthesia.

There is the production of counter-regulatory hormones, including reduced insulin production in insulin-independent hypoglycemia with increasing glucagon production. There is also the production of growth hormone and ACTH-induced cortisol in response to insulin-induced hypoglycemia. If hypoglycemia persists, it leads to neuroglycopenia symptoms comprising drowsiness, confusion, and visual impairment, followed by motor deficit, seizure, and loss of consciousness. Prolonged severe hypoglycemia can lead to multiple organ failure, cardiac arrhythmias, cardiac arrest, and permanent neurological damage.[13][14]

Iatrogenic hypoglycemia can be secondary to exogenous insulin or sulphonylureas. Therefore, there will be raised insulin and suppressed C-peptide levels in the former. In contrast, both insulin and C-Peptide will be raised with a positive sulphonylurea screen in the latter.

Pathophysiology of non-insulin mediated hypoglycemia varies depending upon causative factors and is described as follows:[15][16]

• Alcohol: It inhibits gluconeogenesis and glycogenolysis. Patients intoxicated with alcohol have relatively low glycogen reserves, and alcohol also inhibits the shivering reflex, which leads to a poor endogenous response to hypoglycemia.
• Liver failure: It leads to diminished glycogen stores and impaired gluconeogenesis.
• Renal failure: Hypoglycemia is rare but combined with the loss of renal gluconeogenesis and malnutrition, reduced insulin clearance by the kidney, and reduced metabolism of medication, can cause hypoglycemia.
• Primary adrenal failure: Due to a lack of glucocorticoid hormone, there is decreased glucose production and increased insulin sensitivity. 
• Cerebral malaria: It is poorly understood. However, it is proposed that hypoglycemia can occur due to possible glucose consumption by parasites or the effect of quinine.
• Anterior pituitary failure: Hypoglycemia can occur due to corticotropic and somatotropic hormone deficiency.
• Drug-induced hypoglycemia: The cause of hypoglycemia can be multifactorial and varies with the type of drug.
• Infection: Severe infection can cause decreased glycogen storage and gluconeogenesis with excessive utilization.
• Neoplasia related (Non-Islets cell tumor): Hypoglycemia due to non-islet cell tumor is mediated via increased production of insulin-like growth factor II (IGF-2). IGF-2 stimulates insulin receptors due to its similarity to Insulin.
• Glycogen storage disease: Hypoglycemia occurs due to impaired glucose regulation by the liver.
• Insulin/insulin receptor antibodies: Hypoglycaemia occurs with elevated insulin levels and incompletely suppressed C-peptide levels. Insulin levels are more markedly elevated in those with insulin antibodies, whilst they are mildly elevated in those with insulin receptor antibodies.
• Gastric bypass surgery: The pathophysiology is still unclear. Hypoglycemia occurs in the postprandial phase. The mechanism is likely due to an altered rate of digestion and secretion of insulin.[17]

History and Physical

Hypoglycemia presents with varied symptoms. It involves autonomic (cholinergic and adrenergic) and, if it gets severe, leads to neuroglycopenic symptoms. Therefore, hypoglycemia fulfilling Whipple's triad (as described below) needs further evaluation. Whipple’s triad includes the following:

1. Symptoms and signs consistent with hypoglycemia
2. Biochemical evidence (capillary blood glucose or venous glucose) of hypoglycemia
3. Resolution of symptoms with correction of hypoglycemia

The patient may give a history of autonomic (shaking, sweating, palpitation, anxiety, hunger, paresthesis) and neuroglycopenic (drowsiness, feeling dizzy, generalized or focal weakness, seizure, and confusion) symptoms. It is important to take a detailed history, including the age of onset, nature, and timings of symptoms. Hypoglycemia is classified into reactive (post meals) or fasting hypoglycemia. Weight gain is seen in Insulinoma, whereas neoplasia is frequently associated with weight loss. The existence of underlying illnesses or conditions, drug history, and family history is important in history. It is important to find out about recent gastrointestinal surgery, e.g., gastric bypass. Other signs related to causative factors, including hyperpigmentation (Addison’s disease), other auto-immune diseases, and a history of previous gastric bypass.

Infants and children with hypoglycemia usually have an inborn error of metabolism (IEM), and it is associated with other features including hepatomegaly (glycogen storage disease), seizures (hereditary fructose intolerance), weight loss, vomiting and cataract (galactosemia), and short stature (growth hormone deficiency).[15]

Signs of hypoglycemia are non-specific but include sweating, pallor, tachycardia, raised blood pressure, confusion, and impairment in cognition. These signs are reversible once blood glucose levels are normalized. Prolonged hypoglycemia can result in neurological damage, which can be permanent though this is rare. Physical evaluation involves full general physical examination, including weight and height measurement. It should include signs of auto-immune disease—abdominal exam to look for hepatomegaly and previous surgical scars.

Evaluation

Patients presenting with the features of Whipple’s triad require further evaluation for the underlying cause of hypoglycemia. Initial laboratory investigations include:

• Urea & electrolytes
• Liver function tests
• Fasting glucose
• Insulin, C-peptide, and proinsulin levels at the time of documented hypoglycemia
• Sulfonylurea and meglitinide screen
• Beta-hydroxybutyrate (BOHB)
• Early morning cortisol (if indeterminate, then a short Synacthen test should be arranged) and IGF-1 levels
• IGF-2 levels if there is a history of weight loss and malignancy
• Insulin/insulin receptor antibodies if elevated insulin levels/partially suppressed C-peptide

Reactive Hypoglycemia

It is normally postprandial and mostly due to Islet cell hyperplasia (enlarged and increased number of insulin-producing islet cells), autoimmune syndrome due to anti-insulin antibodies (rise in blood glucose post meals causes fluctuation in insulin production), glycogen storage disease (glucose regulation by the liver is altered) and gastric surgery (altered rate of digestion and secretion of insulin). A mixed meal test is performed for further evaluation in an adult with features suggestive of reactive hypoglycemia.

Fasting Hypoglycemia

Insulinoma, neoplasia, alcohol, and drugs are examples of conditions that lead to fasting hypoglycemia. A 72 hour fast is the gold standard test for the biochemical confirmation of insulinoma. Elevated insulin and C-peptide levels, in the setting of hypoglycemia, with a negative sulfonylurea screen support the diagnosis of endogenous overproduction of insulin(insulinoma). Insulin has an anti-ketogenic effect, and plasma beta-hydroxybutyrate levels remain less than 2.7mmol/L in insulinoma in prolonging fast.

Computed tomography (CT), magnetic resonance imaging (MRI), and abdominal ultrasonography are primary investigations to localize insulinoma. In patients with endogenous hyperinsulinemic hypoglycemia with negative non-invasive localization studies, endoscopic ultrasonography (EUS) or selective arterial calcium stimulation test (SACST) with hepatic venous sampling can be performed for localization of smaller insulinomas. Endoscopic ultrasonography and selective arterial calcium stimulation test (SACST) have shown sensitivity for localization of 82 to 85% and 93%, respectively.[18][19]

Patients diagnosed with insulinoma should be screened for primary hyperparathyroidism and pituitary disease as part of Multiple endocrine neoplasia type 1.

Hypoglycemia Secondary to IEM

Inborn errors of metabolism are rare causes of hypoglycemia. Diagnostic workup is described as below, and further testing should be conducted if suspected.[20]

• Glycogen storage disease: fasting hypoglycemia with hepatomegaly, which can be investigated with a glucose tolerance test with lactate and ketones measurement.
• Glucokinase activating mutation: postprandial hypoglycemia, which can be investigated with a mixed meal test.
• Monocarboxylate 1 mutation (MCT1): autosomal dominant associated with exercise-induced hypoglycemia
• Fatty acid oxidation defect: fasting hypoglycemia with raised cyclic phosphokinase and free fatty acid levels
• Gluconeogenesis disorder: fasting hypoglycemia with raised alanine, glycerol, lactate, and ketones.

Treatment / Management

Generally, hypoglycemia can be managed in non-diabetic patients by eating smaller meals more regularly, with one to two snacks. Patients should be advised to avoid foods rich in sugar and avoid alcohol and caffeine. Treatment of non-diabetic hypoglycemia depends on causative factors. Drugs causing hypoglycemia need to be discontinued. Reactive hypoglycemia post gastric bypass is controlled by dietary modification (low glycemic index diet) and acarbose (an alpha-glucosidase inhibitor). If disabling hypoglycemia persists post dietary and pharmacologic therapy, restoration of gastric constriction and subtotal pancreatectomy are recommended.[21][22](A1)

Surgical resection is the primary treatment modality for insulinomas. In patients with increased surgical risk, medical therapies, such as diazoxide, somatostatin analogs (octreotide, lanreotide), verapamil, phenytoin, and everolimus [an inhibitor of the mammalian (mechanistic) target of rapamycin (mTOR)], have been used with some success.[23]

In one study, ultrasound-guided fine needle chemical ablation with alcohol has successfully resolved hypoglycemia.[24]

In infants and children with inborn errors of metabolism, the following measures should be taken:[15]

• Galactosemia: Milk-free diet
• Hereditary fructose intolerance: Eliminating fructose from the diet
• Glycogen storage disease: High protein with frequent low carbohydrate meals
• Hormone replacement in cortisol and growth hormone deficiency
• Nesidioblastosis: Diazoxide and surgical resection of the pancreas

Differential Diagnosis

The differential diagnoses of hypoglycemia can be divided as low glucose without symptoms or normal glucose with symptoms. It is described in detail as follows:

Low Asymptomatic Glucose

The artefactual low glucose without any symptoms can be observed if a sample is taken without an antiglycolytic agent such as fluoride in the blood collection tube and delayed processing.[25] It is also observed in patients with leukemia or severe hemolytic disease due to the rapid glucose uptake. 

Symptomatic Normal Glucose

Normal plasma glucose with autonomic symptoms (tremors, palpitations, sweating, anxiety, and hunger) can be seen with other conditions as follows:

• Postprandial syndrome
• Cardiac disease (arrhythmia, valvular disease)
• Hyperthyroidism
• Pheochromocytoma
• Medications
• Psychiatric disease

Prognosis

The prognosis of non-diabetic hypoglycemia varies, depending on the cause. Hypoglycemia secondary to IEM needs lifelong treatment and follow-up. Hypoglycemia secondary to hormone deficiency responds well to replacement. Drug-induced or factitious hypoglycemia requires stopping the offending medication.

The prognosis of insulinoma is dependent on staging. Most patients with benign insulinomas have favorable outcomes with surgical resection. However, the prognosis is variable in patients with malignant insulinoma.[8][26] Prognosis of non-islet tumor-related hypoglycemia depends if complete surgical resection is possible. Complete surgical resection can be curative in most cases. However, subtotal surgical resection may improve the symptoms. Recurrence of hypoglycemia is possible and may require medical treatment such as steroids.[27]

The prognosis of hypoglycemia due to bariatric surgery is variable and may require reversal of the procedure.[16]

Complications

Major complications of untreated hypoglycemia include:

• Anxiety
• Seizure
• Confusion or cognitive impairment
• Collapse and coma
• Cardiac arrhythmias and cardiac arrest
• Multi-organ failure
• Weight loss or gain
• Death