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HYPOGLICEMIA Clinical History

Symptoms of hypoglycemia may be categorized as neurogenic (adrenergic) or neuroglycopenic. o Symptoms due to sympatho-adrenal activation include sweating, shakiness, tachycardia, anxiety, and a sensation of hunger.
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Neuroglycopenic symptoms include weakness, tiredness, or dizziness; inappropriate behavior (sometimes mistaken for inebriation), difficulty with concentration; confusion; blurred vision; and, in extreme cases, coma and death. The timing of onset of these symptoms relative to the time of meal ingestion is crucial in the evaluation of a patient with hypoglycemia. Fasting hypoglycemia typically occurs in the morning before eating or during the day, particularly in the afternoon if meals are missed or delayed. Postprandial hyperglycemia typically occurs 2-4 hours after eating food, especially when meals contain high levels of simple carbohydrates. Postprandial symptoms are typically due to reactive causes, but some patients with insulinoma also may present with postprandial symptoms. About 4-6 hours after food ingestion, plasma glucose concentrations are 80-90 mg/dL, and rates of glucose utilization and production are approximately 2 mg/kg/min. Glucose production is primarily (70-80%) from hepatic glycogenolysis, with a lesser contribution (20-25%) from hepatic gluconeogenesis.

Reactive hypoglycemia seldom causes glucose levels to drop low enough to induce severe neuroglycopenic symptoms; therefore, a history of true loss of consciousness is highly suggestive of an etiology other than reactive hypoglycemia. Reactive hypoglycemia has been suggested to be more common in people who are insulinresistant, and it may be a frequent precursor to type 2 diabetes. Therefore, patients who have a family history of type 2 diabetes or insulin-resistance syndrome (ie, hypertension, hyperlipidemia, obesity) may be at higher risk for developing hypoglycemia. In a study of maternal hypoglycemia, Pugh et al investigated risk factors for and results of hypoglycemia in pregnancy.9 Reporting on 870 obstetric patients, 436 of whom were identified as having hypoglycemia following a glucose challenge test (GCT) and the rest of whom were not hypoglycemic following a GCT, the authors found that hypoglycemia occurred more frequently in women below age 25 years and in women who had a preexisting medical condition. Hypoglycemia was less frequent in women whose prepregnancy body mass index was 30. The investigators also found that patients with hypoglycemia were at greater risk ofpreeclampsia/eclampsia.

Physical Physical examination usually does not yield specific findings. Causes

Fasting hypoglycemia

Nesidioblastosis is characterized by a diffuse budding of insulin-secreting cells from pancreatic duct epithelium and pancreatic microadenomas of such cells; it is a rare cause of fasting hypoglycemia in infants and an extremely rare cause in adults. Causes of fasting hypoglycemia usually diagnosed in infancy or childhood include inherited liver enzyme deficiencies that restrict hepatic glucose release (deficiencies of glucose-6-phosphatase, fructose-1,6-diphosphatase, phosphorylase, pyruvate carboxylase, phosphoenolpyruvate carboxykinase, or glycogen synthetase). Inherited defects in fatty acid oxidation, including that resulting from systemic carnitine deficiency and inherited defects in ketogenesis (3-hydroxy-3-methylglutaryl-CoA lyase deficiency) cause fasting hypoglycemia by restricting the extent to which nonneural tissues can derive their energy from plasma FFA and ketones during fasting or exercise. This results in an abnormally high rate of glucose uptake by nonneural tissues under these conditions. Drugs - Ethanol, haloperidol, pentamidine, quinine, salicylates, and sulfonamides

Exogenous insulin
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Insulin-producing tumors of pancreas: Islet cell adenoma or carcinoma (insulinoma) is an uncommon and usually curable cause of fasting hypoglycemia and is most often diagnosed in adults. It may occur as an isolated abnormality or as a component of the multiple endocrine neoplasia type I (MEN) syndrome. Carcinomas account for only 10% of insulin-secreting islet cell tumors. Hypoglycemia in patients with islet cell adenomas results from uncontrolled insulin secretion, which may be clinically determined during fasting and exercise. Approximately 60% of patients with insulinoma are female. Insulinomas are uncommon in persons younger than 20 years and are rare in those younger than 5 years. The median age at diagnosis is about 50 years, except in patients with MEN syndrome, in which it is in the mid 20s. Ten percent of patients with insulinoma are older than 70 years. Nonbeta-cell tumors: Hypoglycemia may also be caused by large noninsulin-secreting tumors, most commonly retroperitoneal or mediastinal malignant mesenchymal tumors. The tumor secretes abnormal insulinlike growth factor (large IGF-II), which does not bind to its plasma binding proteins. This increase in free IGF-II exerts hypoglycemia through the IGF-I or the insulin receptors. The hypoglycemia is corrected when the tumor is completely or partially removed and usually recurs when the tumor regrows.

Autoimmune hypoglycemia - Insulin antibodies and insulin receptor antibodies Surreptitious sulfonylurea use/abuse Hormonal deficiencies - Hypoadrenalism (Cortisol), hypopituitarism (growth hormone) (in children), glucagons deficiency (rare), and epinephrine (very rare) Critical illnesses - Cardiac, hepatic, and renal diseases; sepsis with multiorgan failure Combination of one or more of the above, for example, chronic renal failure and sulphonylurea ingestion Reactive hypoglycemia

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Idiopathic Alimentary hypoglycemia is another form of reactive hypoglycemia that occurs in patients who have had prior upper GI surgical procedures (gastrectomy, gastrojejunostomy, vagotomy, pyloroplasty) and allows rapid glucose entry and absorption in the intestine, provoking excessive insulin response to a meal. This may occur within 1-3 hours after a meal. Very rare cases of idiopathic alimentary hypoglycemia occur in patients who have not had GI operations. Congenital enzyme deficiencies - Hereditary fructose intolerance, galactosemia, and leucine sensitivity of childhood: In hereditary fructose intolerance and galactosemia, an inherited deficiency of a hepatic enzyme causes acute inhibition of hepatic glucose output when fructose or galactose is ingested. Leucine provokes an exaggerated insulin secretory response to a meal and reactive hypoglycemia in patients with leucine sensitivity of childhood.

Workup Laboratory Studies

During hypoglycemic episodes, patients should test their glucose at home to document hypoglycemia that is occurring with the episodes. Take into consideration that meter readings may not be accurate enough to establish the diagnosis. Test glucose and insulin levels simultaneously to document low glucose levels occurring in conjunction with inappropriate insulin levels. Administer an oral glucose tolerance test if reactive hypoglycemia is suspected. An oral glucose tolerance test provides little benefit for the evaluation of fasting hypoglycemia. Perform the test for 5 hours while simultaneously testing glucose and insulin levels. To be meaningful, low blood sugar during the test should be accompanied by typical symptoms. Response to a mixed meal may be more representative. A supervised fast is the most reliable diagnostic test for the evaluation of fasting hypoglycemia. Continue the fast for as long as 72 hours or until symptoms develop in the presence of hypoglycemia (blood sugar <45 mg/dL for women, <55 mg/dL for men). Obtain simultaneous insulin levels every 6 hours, when glucose is low and when symptoms develop. Glucose and/or glucagon must be administered after blood sample withdrawal to abort hypoglycemic symptoms. Obtain C-peptide levels any time an elevated insulin level is obtained. Endogenous hyperinsulinemia from insulinoma is associated with elevated C-peptide concentrations with concurrent hypoglycemia. Exogenous hyperinsulinemia from injected insulin results in low concentrations of C-peptide, both because of the effect of the associated hypoglycemia and because of the direct suppressive effect of insulin on the pancreatic beta cell. 7 Other causes of hypoglycemia should be properly investigated. For example, a morning cortisol level determination and/or adrenocorticotropic hormone (ACTH) stimulation testing should be performed if adrenal insufficiency is suspected. Remember that whole blood glucose values may be spuriously low in polycythemia rubra vera because of the unequal distribution of glucose between erythrocytes and plasma, excessive

glycolysis by erythrocytes, or both. Low blood glucose values in leukemia are due to excessive glycolysis by leukocytes and in hemolytic crisis from excessive glycolysis by nucleated erythrocytes. In the polycythemic patient or in serum of the leukemic or hemolytic patient, prompt measurement of glucose in plasma to which an antiglycolytic agent has been added should provide accurate results. Imaging Studies

For the evaluation of insulinomas, CT scan and ultrasound often are not helpful because most of these tumors are small. MRI may be better. Selective arteriography often is helpful. Selective percutaneous transhepatic venous sampling often is helpful for localizing an insulinoma to the head, body, or tail of the pancreas. Octreotide scanning localizes insulinomas in approximately half the cases. Intraoperative ultrasound can be used as a diagnostic aid. Retroperitoneal tumors that are producing insulin-like growth factor (IGF) usually are imaged easily using a CT scan.

Other Tests

Proinsulin normally represents less than 20% of total immunoreactive insulin. In patients with islet-cell tumors, proinsulin may contribute as much as 70% of insulin immunoreactivity. Provocative tests involving the administration of arginine, leucine, calcium, glucagon, or tolbutamide generally are of limited value because their sensitivity or specificity is inadequate. 10 Diagnostic algorithm: A systematic, algorithmic approach, as shown below, is often required to establish the true cause of hypoglycemia.

Medical Care If dietary therapy is inadequate, medical care for patients with fasting hypoglycemia may include intravenous (IV) glucose infusion. However, IV octreotide is effective for suppressing endogenous insulin secretion. Reactive hypoglycemia does not require medical care. Surgical Care Definitive treatment for fasting hypoglycemia caused by a tumor is surgical resection. The success rate is good for benign islet-cell adenomas, and the success rate for malignant islet-cell tumors can be as high as 50%. Diet

Dietary therapy may be effective for improving symptoms in patients with fasting hypoglycemia. Frequent meals/snacks are preferred, especially at night, with complex carbohydrates. For patients with reactive hypoglycemia, initiate a carbohydrate restriction. Patients should avoid simple sugars, increase the frequency of their meals, and reduce the size of their meals. Patients may require 6 small meals and 2-3 snacks per day.

Activity Because exercise burns carbohydrates and increases sensitivity to insulin, patients with fasting hypoglycemia should avoid significant activity. On the other hand, patients with reactive hypoglycemia often find that their symptoms improve after embarking on a routine exercise program. Medication The goals of pharmacotherapy are to reduce morbidity and to prevent complications. Inhibitors of insulin secretion These drugs increase glucose levels by reducing peripheral glucose metabolism.

Diazoxide (Hyperstat) Can help improve symptoms of hypoglycemia caused by increased insulin secretion in patients awaiting surgery or those with nonresectable disease. Increases blood glucose by inhibiting pancreatic insulin release and, possibly, through an extrapancreatic effect. With normal renal function, hyperglycemic effects start within 1 h and usually last a maximum of 8 h.

Dosing Interactions Contraindications Precautions Adult IV: 100-200 mg bid/tid; refractory hypoglycemia PO: Usually 300-400 mg/d; may be as high as 800 mg Pediatric Infants and newborns: Children: Administer as in adults Interactions Highly bound to serum proteins and displaces other substances that also are highly bound (eg, Coumadin), resulting in higher levels; may decrease serum hydantoins, possibly resulting in decreased anticonvulsant effects; thiazide diuretics may potentiate hyperuricemic and antihypertensive effects Contraindications Documented hypersensitivity; pheochromocytoma Precautions aortic coarctation, aortic aneurysm, arteriovenous shunts, 8-15 mg/kg/d IV q8-12h may require higher dosages

Pregnancy C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus Precautions Causes salt and water retention; caution in congestive heart failure or decreased cardiac output; causes relaxation of smooth muscle in peripheral arterioles, leading to hypotension; do not administer within 6 h of administering beta-blockers, hydralazine, methyldopa, minoxidil, nitrites, prazosin, reserpine, and papaverinelike compounds; patients with diabetes mellitus may require treatment for hyperglycemia; when given prior to delivery, may produce fetal or neonatal hyperbilirubinemia, thrombocytopenia, altered carbohydrate metabolism, and other adverse reactions Octreotide (Sandostatin) Acts primarily on somatostatin receptor subtypes II and V. Inhibits GH secretion and has a multitude of other endocrine and nonendocrine effects, including inhibition of glucagon, VIP peptides, and GI peptides. Dosing Adult Initial: 50 mcg SC tid; may increase dose to 500 mcg SC tid; doses of 300-600 mcg/d or higher seldom result in additional biochemical benefit Pediatric 1-10 mcg/kg SC tid Interactions May reduce effects of cyclosporine; patients on insulin, oral hypoglycemics, beta-blockers, and calcium channel blockers may need dosage adjustments Contraindications Documented hypersensitivity Precautions Pregnancy B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals Precautions Biliary tract abnormalities (eg, stones, sludge, biliary duct dilatation) can occur; adverse effects primarily related to altered GI motility include nausea, abdominal pain, diarrhea, increased incidence of gallstones, and biliary sludge; because of alterations in counter-regulatory hormones (eg, insulin, glucagon, GH), hypoglycemia or hyperglycemia may occur; bradycardia, cardiac conduction abnormalities, and arrhythmias have been reported; because of inhibition of TSH secretion, hypothyroidism may occur; caution in renal impairment; cholelithiasis may occur

Follow-up Further Outpatient Care

If the patient has fasting hypoglycemia and the cause is treatable, long-term follow-up usually is not needed. If the cause cannot be treated definitively (eg, inoperable pancreatic insulinoma), diazoxide can be used to elevate blood glucose levels and chemotherapy that specifically targets the beta cell (ie, using cytotoxic agents such as streptozotocin) should be considered. If the patient has reactive hypoglycemia, periodic outpatient monitoring is warranted to assess the continued presence of symptoms.

Complications

Untreated fasting hypoglycemia can lead to severe neuroglycopenia and, possibly, death. Untreated reactive hypoglycemia may cause significant discomfort to the patient, but long-term sequelae are not likely.

Prognosis

Prognosis depends on the cause of the hypoglycemia. If the cause of fasting hypoglycemia is identified and curable, prognosis is excellent. If the problem is not curable, such as an inoperable malignant tumor, long-term prognosis is poor. However, note that these tumors may progress rather slowly. If the patient has reactive hypoglycemia, symptoms often spontaneously improve over time, and long-term prognosis is very good.

Patient Education For excellent patient education resources, visit eMedicine's Diabetes Center. Also, see eMedicine's patient education article, Hypoglycemia (Low Blood Sugar).