Hypoglycemia overview

# Overview
Hypoglycemia is a pathologic state induced by a lower than normal level of glucose in the blood. It happens usually when blood glucose level is less than 60 or 70 mg/dL, different values (typically below 40, 50, 60, or 70 mg/dL) have been defined as low. Patients with type 1 diabetes may suffer an average of two episodes of symptomatic hypoglycemia per week, thousands of such episodes over a lifetime of diabetes, and one episode of severe symptoms per year. Causes of hypoglycemia depend on age; neonatal causes are transient neonatal hypoglycemia, prematurity, intrauterine growth retardation, perinatal asphyxia, sepsis, congenital hypopituitarism, congenital hyperinsulinism, infant of a diabetic mother, Beckwith-Wiedemann syndrome and inborn errors of carbohydrate metabolism. Adult hypoglycemia caused mainly by insulin or insulin secretagogue drugs, alcohol, hepatic failure, renal failure, cardiac failure, sepsis, non-islet cell pancreatic tumors, insulinoma, and reactive hypoglycemia. The pathophysiology of hypoglycemia depends on the failure of physiological defense mechanisms and hormones, such as insulin, glucagon, and epinephrine to correct hypoglycemia. Most of these defense mechanisms are hormones that control glycogenolysis and gluconeogenesis. No single value alone serves to define the hypoglycemia. Accordingly, diagnostic criteria (Whipple's triad) is needed to diagnose hypoglycemia. Complications in adults include increased risk of dementia, cardiovascular complications and maybe death. Prognosis is generally good with prompt treatment. However, 4-10% of deaths of patients with type 1 diabetes are due to hypoglycemia. Screening of hypoglycemia should be obtained in infants who are at risk for hypoglycemia. Surveillance should be continued every three to six hours for the first 48 hours of life. Medical treatment of hypoglycemia depends on the severity of symptoms and etiology. If asymptomatic, repeating the measurement in short time and avoiding critical tasks. Twenty grams of glucose is usually sufficient to raise the blood glucose in a severe hypoglycemic and symptomatic patients. Glucose should be administered subcutaneously or intramuscularly or 25% of dextrose serum should be given intravenously. In case of postprandial hypoglycemia, the patient should have frequent small meals or snacks and foods should be high in fiber, avoiding foods high in sugar. Surgery is the treatment of choice for insulinoma.

# Historical Perspective
Hypoglycemia is a Greek word that means under-sweet blood. In 1922, hypoglycemia was first discovered by James Collip when he was working on purifying insulin. He injected insulin into a rabbit and realized a reduction in blood glucose levels. Collip injected a large dose of insulin to the rabbit, that lead to coma and death of the rabbit.

# Classification
Hypoglycemia can be classified based on severity into 5 categories, include severe hypoglycemia, symptomatic hypoglycemia, asymptomatic hypoglycemia, probable symptomatic hypoglycemia, and pseudo hypoglycemia. It is also can be classified based on severity into mild, moderate and severe.

# Pathophysiology
The pathophysiology of hypoglycemia depends on the failure of physiological defense mechanisms and hormones such as insulin, glucagon, and epinephrine to correct hypoglycemia. Most of these defense mechanisms are hormones that control glycogenolysis and gluconeogenesis. Insulinoma is a rare benign pancreatic neuroendocrine tumor that arises from  islet cells. It is mediated by a mutation in mTOR/P70S6K signaling pathway. Non-islet-cell tumors(NICTH) are large tumors of mesenchymal or epithelial cell types originate from the pancreas. NICTH appears to be increased glucose utilization and inhibition of glucose release from the liver. This happens as a result of tumor production of incompletely processed IGF-2. On gross pathology insulinomas have a gray to red-brown appearance, encapsulated and are usually small and solitary tumors. Although there is a case report of a large (9cm), pedunculated and weighing more than 100 g. On microscopic histopathological analysis, patterns like trabecular, gyriform, lobular and solid structures, particularly with amyloid in a fibrovascular stroma, are characteristic findings of insulinoma. It is also evaluated for the mitotic index and immunohistochemistry staining by Chromogranin A, synaptophysin, and Ki-67 index.

# Causes
Causes of hypoglycemia depend on age; neonatal causes are transient neonatal hypoglycemia, prematurity, intrauterine growth retardation, perinatal asphyxia, sepsis, congenital hypopituitarism, beta sympathomimetic drugs, congenital hyperinsulinism, infant of a diabetic mother, Beckwith-Wiedemann syndrome and inborn errors of carbohydrate metabolism. Causes of adult hypoglycemia are: insulin or insulin secretagogue drugs, alcohol, hepatic failure, renal failure, cardiac failure, sepsis, non-islet cell pancreatic tumors, insulinoma, reactive hypoglycemia, post gastric bypass hypoglycemia, and autoimmunee hypoglycemia.

# Differentiating Hypoglycemia from other Diseases
Hypoglycemia should be differentiated from other causes of autonomic hyperactivity symptoms. Neonatal hypoglycemia should be differentiated from other causes of neurological symptoms in neonates such as sepsis, metabolic diseases: urea cycle disorders, and branched-chain organic acidemias, hyponatremia and neonatal asphyxia. In adults, hypoglycemia should be differentiated from other diseases that may cause autonomic hyperactivity symptoms, such as hyperthyroidism, anxiety, arrhythmia, and pheochromocytoma.

# Epidemiology and Demographics
Patients with type 1 diabetes may suffer an average of two episodes of symptomatic hypoglycemia per week, thousands of such episodes over a lifetime of diabetes, and one episode of severe symptoms per year. Hypoglycemia is less frequent in type 2 diabetes than it is in type1. Event rate for severe hypoglycemia range from 40 to 100 percent of those in type 1 diabetes. There is no racial or gender predilection of hypoglycemia.

# Risk Factors
Risk factors of hypoglycemia include diabetic patients with excessive insulin doses especially after missed meals or after exercise. Nocturnal fasting and alcohol intake are less common risk factors in diabetic patients.

# Screening
Screening of hypoglycemia should be obtained in infants who are at risk for hypoglycemia. Surveillance should be continued every three to six hours for the first 48 hours of life. Treatment should be started immediately after primary blood test and we should not wait for the confirmatory laboratory results due to high risk of the neurological outcome.

# Natural History, Complications and Prognosis
If left untreated, patients with hypoglycemia may progress to develop anxiety, nervousness, tremor, palpitations, and sweating. Common complications of hypoglycemia include psychomotor retardation, epilepsy and prematurity in neonates. Complications in adults include increased risk of dementia, cardiovascular complications and may be death. Prognosis is generally good. Four to ten percent of death in patients with type 1 diabetes are due to hypoglycemia.

# Diagnosis

## Diagnostic criteria
Diagnostic criteria of hypoglycemia include symptoms of hypoglycemia, a low plasma glucose concentration correlated with symptoms, and correction of glucose level relieves symptoms. These criteria called  Whipple's triad. Neonatal hypoglycemia can be diagnosed by measuring multiple metabolic panels include plasma insulin, plasma C-peptide, beta-hydroxybutyrate, blood pH, bicarbonate, lactate, free fatty acids, acylcarnitine profile, plasma free and total carnitine levels.

## History and Symptoms
Hypoglycemic symptoms and manifestations can be divided into those produced by the counterregulatory hormones: adrenergic symptoms include anxiety, nervousness, tremor, palpitations, sweating, coldness. Glucagon induced manifestations include hunger, nausea, vomiting. Neuroglycopenic Manifestations are irritability, weakness, apathy, lethargy, confusion, and amnesia.

## Physical Examination
Main signs of hypoglycemia are tachycardia and ventricular arrhythmia. Neurological manifestations include altered mental status, hypotonia, focal or general motor deficit and jerks. Neonatal hypoglycemia signs include large for gestational age, hepatomegaly in Beckwith-Wiedemann syndrome and glycogen storage diseases. Ambiguous genitalia, hypertension, hyponatremia, and hyperkalemia are found in congenital adrenal insufficiency.

## Laboratory Findings
Laboratory investigations of hypoglycemia depend on many tests: plasma glucose is usually <55-70 mg/dL, insulin, c-peptide, proinsulin, sulfonylurea screen, beta-hydroxybutyrate, and 24-hour fasting glucose level are another tests that are required to establish the etiology.

## Electrocardiogram
On EKG, hypoglycemia is characterized by sinus tachycardia and supraventricular tachycardia.

## Chest X-Ray
There are no x-ray findings in hypoglycemia.

## CT
CT scan can be used for diagnosing insulinoma and islet-cell hypertrophy. Currently, with the advances in technology. The sensitivity has risen to 80% and 94.4% for helical CT scan with dual-phase multidetector CT scan. Insulinoma is hypervascular and CT shows greater enhancement than rest of the pancreatic parenchyma. It can appear hypovascular and hypodense lesions after the administration of contrast.

## MRI
MRI is helpful in the diagnosis of insulinoma in the case of failed CT. MRI has better sensitivity than CT scan. Insulinoma shows low intensity on T1 weighted and high intensity on T2 weighted signals, having better visualization on T1 and T2 weighted images with fat suppression. Large tumors ( 2 cm) exhibit typically homogenous pattern and ring enhancement. A similar pattern is seen in metastatic lesion as of primary tumor.

## Echocardiography or Ultrasound
Transabdominal ultrasound has low sensitivity varying between 0-66% in detecting insulinoma. The sensitivity increases with the use of more invasive endoscopic ultrasound (93%) and intraoperative ultrasound (86%).We see hypoechoic lesions and hypervascular mass on the ultrasound.

## Other Imaging Findings
There are no other imaging findings associated with hypoglycemia.

## Other Diagnostic Studies
Other tests include: injection of calcium gluconate into splanchnic arteries and venous sampling searching for insulin.

# Treatment

## Medical Therapy
Medical treatment of hypoglycemia depends on the severity of symptoms and the cause. If asymptomatic, repeating the measurement in short time and avoiding critical tasks. Twenty grams of glucose is usually sufficient to raise the blood glucose in a severe hypoglycemic and symptomatic patients. Glucose should be administered subcutaneously or intramuscularly or 25% of dextrose serum should be given intravenously. In case of postprandial hypoglycemia. The patient should have frequent small meals or snacks and foods should be high in fiber, avoiding foods high in sugar. Surgery is the best treatment for insulinoma.

## Surgery
Surgical removal of the insulinoma is the treatment of choice and resection of metastatic liver disease.

## Primary Prevention
The main stay in primary prevention is patient education about symptoms, blood glucose level control, and hypoglycemia treatment. Reactive hypoglycemia prevention depends on changing eating habits to smaller meals and avoiding excessive sugar intake.

## Secondary Prevention
Secondary Prevention is the same as primary prevention.

## Cost-Effectiveness of Therapy

## Future or Investigational Therapies

# Case Studies

## Case #1