Glucose Metabolism Disorders Hypoglycemia

Pathogenesis and Pathophysiology. Unlike other body tissues, the CNS relies almost exclusively on glucose as an energy substrate. CNS features that promote its vulnerability to hypoglycemia include its low glucose level (about 25 percent of the serum glucose value), its inability to store significant glucose as glycogen, and the high cerebral metabolic rate (5 mg/100 g brain tissue/min) for glucose. yj Thus, for a 1400 g brain, the glucose requirement is 70 mg/min. The brain's dependence on glucose, coupled with its limited glycogen stores, results in rapid CNS dysfunction when hypoglycemia occurs and permanent neurological sequelae if it is prolonged. The glucose level at which CNS dysfunction occurs depends on its rapidity of onset, the current level of CNS activity, the quantity of CNS glycogen, and the availability of alternative fuels. The immediate cause of CNS dysfunction is unknown. Although it was initially believed to be due to tissue energy depletion, high-energy organic phosphates are normal during the early stages of symptomatic hypoglycemia. y Alternative explanations include accumulation of metabolic byproducts of nonglucose metabolism, impaired acetylcholine synthesis, and changes in neurotransmitter levels, such as those of glutamate, aspartate, and gamma-aminobutyric acid.y When glucose slowly decreases, the CNS can use nonglucose substrates, especially ketoacids and glucose metabolism intermediaries,1^ as well as several amino acids. y

Epidemiology and Risk Factors. Hypoglycemia is a common problem without predilection for any age, gender, or ethnic group. Although excessive insulin administration is the most common cause of hypoglycemia,^! excessive use of oral hypoglycemic agents is another common cause. The major risk factor for the development of reactive hypoglycemia (infrequent) is GI surgery (e.g., vagotomy and pyloroplasty, gastrectomy, or gastrojejunostomy).

Clinical Features and Associated Disorders. Symptoms of hypoglycemia can be divided into adrenergic and neuroglycopenic (low CNS glucose). The adrenergic symptoms (e.g., diaphoresis, tachycardia, enhanced physiological tremor) are inversely correlated to the rate of development of hypoglycemia, being most pronounced with acute onsets. Hunger, visual disturbances, and altered temperature perceptions are other possible adrenergic features. The neuroglycopenic features include headache, malaise, impaired concentration, confusion, disorientation, irritability, lethargy, stupor, coma, generalized seizures, myoclonus, and psychiatric disturbance. Focal CNS dysfunction, including focal seizures, hemiplegia, paroxysmal choreoathetosis, and patchy brain stem and cerebellar involvement mimicking basilar artery thrombosis, have also been reported. yi With subacute onsets, drowsiness, lethargy, decreased psychomotor activity, and confusion may be observed,y and when chronic, the insidious onset of memory, personality, and behavioral disturbances may suggest dementia. y] The medullary phase of hypoglycemia, characterized by deep coma, pupillary dilatation, shallow breathing, bradycardia, and hypotonicity, occurs at a blood glucose level of around 10

mg/dl.y

Adrenergic features, when present, precede neurobehavioral features, thereby functioning as an early warning system. However, when sympathetic dysfunction (e.g., diabetic autonomic neuropathy) exists or when adrenergic blockers are being used, these features may be inapparent.

Differential Diagnosis and Evaluation. Hypoglycemia may be divided into fasting (the overwhelming majority), reactive (uncommon), and artifactual (,Table,38-12 ). Fasting hypoglycemia is usually the result of exogenous insulin or oral hypoglycemic administration by diabetic patients. Drug-induced hypoglycemia can be caused by pentamidine, nonsteroidal anti-inflammatory drugs, salicylates, sulfonamides, clofibrate, phenytoin, rifampin, thyroid hormone, anabolic steroids, and probenicid. Enzyme defects causing hypoglycemia are rare and typically begin in childhood. By prolonging the half-life of insulin and oral

_TABLE 38-12 -- MAJOR CAUSES OF HYPOGLYCEMIA_

Fasting

Inadequate glucose supply, excessive glucose demand Reactive

Iatrogenic (abrupt discontinuation of total parenteral nutrition) Fructose and leucine intolerance and galactosemia Idiopathic

Artificial (lymphoproliferative disoders)

Data from Black TP Metabolic encephalopathies, In Weiner W J(ed) Emergent and Urgent Neurology Philadelphia, J B Lippincott, 1992, pp 27-57; Lockwood AH toxic and metabolic encephalopathies In Bradley WG, Daroff BB, et al (eds) Neurology in Clinical Practice, 2nd ed Boston, Butteworth-Heinemann 1996,pp 1335-1372; and Yealy DM, Wolfson AB Hypogycemia. Emerg Med Clin North Am 1989;7 837-848

agents, RF may result in hypoglycemia. Liver disease may also cause hypoglycemia in this way while also impairing glucose production and glycogen storage. Disorders of fatty acid utilization increase the need for glucose and may rapidly result in hypoglycemia. Reactive hypoglycemia is most commonly caused by surgical procedures (iatrogenic) that result in rapid gastric emptying, which, in turn, stimulates excessive insulin release, thereby causing hypoglycemia. [116]

The neurological symptoms associated with hypoglycemia primarily reflect CNS involvement (e.g., encephalopathy and seizures) and are related to the rapidity of onset. Diagnostic considerations of patients with hypoglycemia depend on the presenting manifestations (e.g., disorders known to produce seizures; when hypoglycemia is associated with such; or disorders known to produce encephalopathy, when hypoglycemia is associated with confusion).

Evaluation. Whipple's triad (hypoglycemic features, laboratory confirmation of a low serum glucose, and resolution of symptoms with glucose replacement) is diagnostic of hypoglycemia. To identify the underlying cause of hypoglycemia, other studies, including serum studies for C-peptide, proinsulin and insulin levels, antibodies to insulin or its receptor, and sulfonylurea levels, may be required in addition to routine laboratories. Abdominal imaging (CT or MRI) and arteriography, for tumor localization, may be useful. In the evaluation of related neurological symptoms, the EEG reveals generalized slowing, unless the degree of hypoglycemia is mild. In this setting, hyperventilation-induced slowing may persist after hyperventilation is discontinued. In the setting of symptomatic hypoglycemia, the confusional state correlates with EEG slowing. Additionally, seizure activity may be observed. As the glucose level drops further, the comatose state supervenes and burst-suppression activity is demonstrated on the EEG. Intravenous administration of glucose can reverse hypoglycemic seizure activity and coma.

Regarding symptom resolution with glucose replacement, although catecholamine-mediated features usually respond within minutes, the CNS-related features may require longer for resolution. y^ If the CNS features do not resolve within an hour, permanent CNS damage may have occurred. In addition, the possibility that the hypoglycemia is related to another disorder should be considered.

Management. Prevention of serious morbidity and mortality requires early recognition of hypoglycemia and

prompt glucose replacement, regardless of etiology. To avoid masking of the autonomic (warning) features of hypoglycemia, beta blockers should be avoided in patients taking hypoglycemic agents. To prevent the development of Wernicke-Korsakoff's syndrome in alcoholic and malnourished patients, thiamine supplementation (1 mg/kg) should also be administered before giving glucose. Malnourished patients should also receive niacin to prevent pellagra. Depending on the etiology, more specific therapies may be indicated (e.g., corticosteroid replacement for adrenal insufficiency).

Prognosis and Future Perspectives. Hypoglycemia is associated with a substantial morbidity, primarily related to accidents (e.g., vehicular) and seizures with resultant injuries. y] In the setting of hypoxic encephalopathy, premature prognostication should be avoided, given that slow improvement may continue for 1 to 2 years.y When glucose is replaced before the medullary phase is reached, the features may be reversible. After this point, especially if treatment was delayed, recovery may be protracted or incomplete. y The potential risk of glucose administration to euglycemic and hyperglycemic patients is small compared with the potentially substantial benefit. However, the possibility of cerebral ischemia must be considered, because hyperglycemia at the onset of brain ischemia worsens the postischemic outcome, whereas hyperglycemia occurring after experimental cerebral infarction does not. y , '117]

HYPERGLYCEMIA

Diabetic ketoacidosis (DKA) and NKHH, two hyperglycemic syndromes occurring among patients with diabetes, can both present with encephalopathy. In addition, patients with NKHH frequently present in coma or with new-onset seizures. Thus, because neurologists are often summoned early, they must be familiar with these disorders.

Pathogenesis and Pathophysiology. Although the brain tolerates hyperglycemia better than hypoglycemia, encephalopathic features still develop, usually as a reflection of cerebral dehydration (e.g., intravascular hyperosmolality) or cerebral edema (e.g., too-rapid correction of the hyperglycemia). A correlation between the degree of encephalopathy and the serum osmolality exists, the pathophysiology of which has been discussed (see Hyponatremia). In addition to osmotic effects, intravascular coagulation related to hyperviscosity may occur. y

The primary problem in DKA is insulin deficiency. This results in an increased ratio of glucagon to insulin, accelerated gluconeogenesis, enhanced glycogenolysis, and reduced glucose clearance, thereby producing hyperglycemia. [r:&i In addition, insulin deficiency leads to increased fatty acid mobilization and the increased glucagon-to-insulin ratio induces fatty acid oxidation. yj Therefore lipolysis and ketone body formation occur. Once the renal threshold is exceeded, glucosuria occurs,[113] which promotes polyuria, due to osmotic diuresis, and polydipsia. In the setting of NKHH, insulin production is usually sufficient to inhibit lipolysis (i.e., nonketotic) but insufficient to prevent hyperglycemia. As the serum osmolality slowly rises, cerebral idiogenic osmole formation occurs (to prevent dehydration), thereby making the patient susceptible to cerebral edema during rehydration.

Epidemiology and Risk Factors. The major risk factor for the development of hyperglycemia is diabetes mellitus, with a prevalence of about 1 percent in the United States. NKHH accounts for 10 to 20 percent of all cases of severe hyperglycemia, yj a value that is decreasing due to earlier detection of uncontrolled hyperglycemia.^ Because of the high glucose content of total parenteral nutrition, patients receiving this type of therapy are also at risk of developing hyperglycemia. The incidence of gestational diabetes (carbohydrate intolerance that is present only during pregnancy) ranges from 1 percent in predominantly rural areas to 12 percent in racially mixed urban areas. y,1

Clinical Features and Associated Disorders. The general medical features of hyperglycemia include polyuria, polydipsia, and anorexia. Patients with DKA tend to be younger, type I diabetics, with a symptom onset measured in days. At onset, the mental status varies from normal (20 percent) to comatose (10 percent) and correlates most to the level of hyperosmolality.y1 DKA is frequently precipitated by infection or noncompliance with insulin therapy. Patients with NKHH tend to be older, type II diabetics with more pronounced dehydration. Unlike patients with DKA, focal neurological abnormalities, seizures (both focal and generalized), and coma are commonly observed. The most common precipitants of NKHH are infection, chronic renal insufficiency, GI bleeding, pancreatitis, stroke, burns, and certain medications.[120]

Differential Diagnosis. Although patients who present with encephalopathy may easily be diagnosed with hyperglycemia as the cause, diagnostic difficulty arises when encephalopathic patients present without a history of diabetes. Blood glucose determinations must be performed on all encephalopathic patients, and when they are shown to be hyperglycemic, DKA and NKHH, in addition to uremia, hepatic failure, toxin ingestion, starvation ketosis, alcoholic ketoacidosis, lactic acidosis and other causes of encephalopathy, must be excluded. A history of ethanol abuse and, typically, a lack of hyperglycemia helps differentiate alcoholic ketoacidosis. Evidence of renal dysfunction and the absence of ketones helps differentiate uremia, and starvation ketosis is not associated with hyperglycemia.

Evaluation. In evaluating patients with hyperglycemic-induced encephalopathy, precipitating factors and secondary disturbances should be sought, including electrolyte disturbances (hypokalemia, hypophosphatemia, hypomagnesemia), infection (leukocytosis, urinalysis, chest x-ray study, blood and urine cultures), and hypokalemic-induced EKG changes. In addition, ABGs and serum osmolality, as well as renal and hepatic function, should be assessed. Hyperamylasemia, seen in nearly 80 percent of patients with DKA, may result in an incorrect diagnosis of pancreatitis. [11Ma] Typical laboratory features in patients with DKA include blood glucose above 400 mg/dl, arterial blood pH below 7.2, bicarbonate below 10 mEq/L, and an elevated serum osmolality (usually below 350 mOsm/L). Ketone bodies and beta-hydroxybutyrate are elevated in the blood and urine, and there is a marked glycosuria. [113] In patients with NKHH, the blood glucose level is usually above 800 mg/dl and the osmolality above 350 mOsm/L.y

Management. If encephalopathic features are noted in a known diabetic, 25 g of dextrose should be administered intravenously because hypoglycemia is the most common

cause of mental status changes and this dosage will not cause harm in the setting of DKA. y^ The primary treatment of DKA is insulin replacement, which facilitates glucose uptake and glycogen formation, and reduces the rate of ketone body formation. Volume repletion initially requires NS, because most patients have TBW deficits of roughly 5 L. [118] This also lessens the degree of cerebral edema. Half-normal saline can be substituted once the orthostasis resolves, and 5-percent dextrose can be added after the glucose drops to 250 mg/dl or below. Although cerebral edema is a concomitant of treatment, a malignant increase in cerebral edema may occur, with resultant increased ICP, rapid deterioration, and death. [113] In this setting, aggressive treatment of cerebral edema must be undertaken, typically with hyperventilation, mannitol administration, and ICP monitoring. Because the major problem in patients with NKHH is dehydration, the primary treatment is rehydration, followed by insulin therapy and correction of underlying illnesses. Normal saline is the fluid of choice, and once blood glucose levels reach 250 mg/dl, 5-percent dextrose is provided to avoid hypoglycemia.

Seizure control requires normalization of serum osmolality and glucose. Standard antiepileptic drugs are ineffective, and furthermore, some antiepileptic drugs, such as phenytoin, can inhibit the release of endogenous insulin. yj In DKA, the rate of patient mortality remains significant (6 to 9 percent), with most deaths related to cardiovascular or cerebral complications, or the precipitating factor. [1131 Mortality rates as high as 40 to 70 percent are reported for NKHH.

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