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Hypoglycemia: A Brief Review
Hypoglycemia: A Brief Review c.
K. GORMAN, M.D., PH.D.*
HYPOGLYCEMIA
The lower limit of the normal "true" fasting blood sugar is 60 mg. per 100 ml.; by definition, anything below that level represents hypoglycemia. However, by usage "hypoglycemia" has become synonymous with "hypoglycemic" reaction, which is the term used to cover the complex of symptoms and signs which develop when the blood sugar falls to abnormally low levels. The condition can be subdivided into two main categories, (i) that due to the commonly used "therapeutic" hypoglycemic agents, and (ii) spontaneous hypoglycemia and that due to idiosyncratic reaction to drugs and other substances. The major emphasis in this paper will be on the hypoglycemia that occurs as a complication of the treatment of diabetes mellitus. Hypoglycemia as a Complication of the Treatment of Diabetes Mellitus
Before the discovery of insulin, the diagnosis of hypoglycemia was a rarity; the condition was recognized only in diabetics being treated by undernutrition. 25 Since 1922, the condition has become common and still remains the greatest hazard of insulin therapy. The resultant familiarity with the symptoms has, however, allowed hypoglycemia to be recognized in many diseases unrelated to diabetes mellitus. Causes of Hypoglycemia in Diabetes
Insulin therapy is the commonest cause of hypoglycemia in diabetics. The susceptibility to insulin reactions and the time of their onset are influenced by many factors. Reactions due to regular insulin in the normal dose range occur approximately two to six hours after injection. Where large doses of highly concentrated (e.g., 500 units/ml.) regular insulin are used, as in insulin resistance, the action is more prolonged, and reactions can occur at any time of the day. Reactions due to the intermediate-action insulins (N.P.H. and lente) are commonest in the afternoon and evening,
* Assistant
Resident in Medicine, Toronto General Hospital, Toronto, Ontario, Canada. Formerly, Fellow in Medicine, Joslin Clinic, Boston, Massachusetts
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whereas those due to the long-acting varieties (protamine zinc and ultralente) occur at night or in the early morning. The omission of a meal, or unaccustomed exercise will help to precipitate a reaction at any time. Hypoglycemia is being recognized more often in patients being treated with the oral hypoglycemic agents. It was initially thought that these drugs could not cause frank hypoglycemia in diabetics. However, one report4 cites an incidence of reactions in as many as 6 per cent of such patients, and this diagnosis should be kept in mind as an explanation of unusual behavior, or stroke-like states in these people. Symptoms
The blood sugar level at which a hypoglycemic reaction develops is, within limits, variable, and the severity of the reaction is not always proportional to the degree of hypoglycemia. Adults tend to experience symptoms earlier than do children. In the adults, a true blood sugar of 40 mg. per 100 m!. can cause gross confusion, whereas children can behave quite normally with values considerably below this. However, a sudden change from rest to activity in a child in this state may rapidly precipitate the overt signs of hypoglycemia. In both adults and children, a rapid fall in the blood sugar usually produces more severe symptoms, and these may occur in adults even when the blood sugar changes rapidly from hyper- to normoglycemic levels. 30 In contrast, the awareness of symptoms is reduced by treatment with sedatives and monoamine oxidase inhibitors. 8 As a rule, the intermediate and long-acting insulins cause a more gradual onset of symptoms than do the rapidly acting varieties. The early symptoms of hypoglycemia reflect the central effects of the low blood sugar. Himwich21 has reported that these can be divided into five degrees, based on the metabolic requirements of the different areas of the brain. The phylogenetically youngest areas, the cerebral cortex and parts of the cerebellum, had the highest metabolic rates and were the first to suffer, whereas the medulla oblongata, the oldest area and that with the lowest energy requirements, was the last to show impairment. The symptom complexes which vary from one patient to another, and also in the same patient, can be considered under four main headings: 1. Symptoms due to the effects of hypoglycemia on the autonomic nervous system
a. Profuse sweating, even on a cold day b. Hunger c. Paresthesias of the lips and fingers d. Pallor e. Palpitations f. A fine tremor 11. Symptoms due to the effects of hypoglycemia on the central nervous system a. Blurring of vision and diplopia b. Headaches c. Spastic character in movements, especially in the legs d. Lights appearing to have a diffuse glare, especially at night e. Slow reaction time, e.g., when driving or participating in athletic activities f. Frequent and uncontrolled yawning
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Ill. Psychic changes due to hypoglycemia
a. Depression and irritability b. Drowsiness in the normal waking hours and inability to sleep at night c. An unaccustomed inability to concentrate on or comprehend a problem IV. Symptoms due to the effects of hypoglycemia on the muscular system a. Weakness and easy fatigability during heavy physical activity
A patient may experience some or even all of these symptoms during a hypoglycemic reaction. Signs of Hypoglycemia The symptoms mentioned above are experienced in the early stages of hypoglycemia, when the patient is still fully conscious and cooperative. If these are not recognized and the reaction becomes more severe, signs, rather than symptoms, become the clue to diagnosis, since, with the depression of cerebral function, the patient is unable to describe his sensations. The signs which develop are essentially physical manifestations of the symptoms and are not infrequently noticed by casual observers before the patient is aware of any change. When undisturbed, the patient may be unusually quiet and withdrawn, but slight excitement can produce violent activity. Tachycardia is common, as are ventricular premature beats, and electrocardiographic changes have been reported. These consist of S.T. depression in the standard limb and lateral chest leads. Hypoglycemia has been said to cause angina pectoris but has been absent in experimental studies. 12 . 22 Hypoglycemia is a cause of hypokalemia, and it is probable that the E.C.G. changes are secondary to this, since the prior administration of potassium prevents them. 12 Hypothermia is probably commoner in hypo glycemia than is generally recognized, and in some cases it has been an aid to the diagnosis. 26 Involuntary twitching is common, and the patient often manifests sensory aphasia, apraxia and emotionallability. Choreiform and athetoid movements and clonic or tonic seizures may develop. Transient mono- and hemiplegias can occur, particularly in patients suffering from cerebral arteriosclerotic vascular disease. Some patients become frankly psychotic; it has not been established whether there is, in them, an underlying psychiatric disorder which has simply been revealed by the hypoglycemia. Hysteria, catatonia and dementia have been observed. 30 Children who are prone to convulsive reactions have in some cases been found to have abnormal electroencephalograms suggestive of epileptic activity;18 some of these patients have been helped by anticonvulsant drugs. As the hypoglycemia progresses and the patient becomes unconscious, sphincter control may be lost, with consequent involuntary micturition and defecation. At this stage the patient cannot be roused by painful stimuli, the pupils are dilated but react to light, the deep tendon reflexes may be absent, and a Babinski sign is present. It is not uncommon to find
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bizarre neurological signs, with absent or unpaired reflexes on one side and a Babinski response on the other. If the hypoglycemia has been sufficiently severe and prolonged, a completely decerebrate picture will develop. Reactions Without Warning
Diabetic patients on insulin therapy have often complained that hypoglycemic reactions develop without any warning symptoms. This complaint is commonest when the diabetes is of greater than 10 years' duration,30 and its frequency appears to be increasing. 40 The condition appears to be due to a lack of sympathetic response to hypoglycemia5 , 40 which is not necessarily associated with any obvious sensory neuropathy. The situation created by these "reactions without warning" is very distressing to the patient. Two therapeutic approaches are necessary: (i) reorganization of the therapeutic regimen to minimize the risk of hypoglycemia and (ii) re-education of the patient. The patient must constantly be on the alert for any unusual symptoms and should follow the maxim that any peculiar sensation is a reaction until proved otherwise. It is most important for him to look for parasympathetic and cerebral signs. If in doubt, he should take 5 to 10 grams of carbohydrates and watch himself closely. It is unlikely that treatment with ephedrin sulfate will have any beneficial effect. Diagnosis of Hypoglycemic Reaction If hypo glycemia is suspected, the urine should be tested. If the first sample contains sugar, another specimen obtained soon afterwards should be tested. If hypoglycemia exists, the second sample will be sugar-free, or at least it will contain much less sugar than the first sample, which may contain urine secreted during an earlier period of hyperglycemia, unless the patient cannot void completely because of a "neurogenic" bladder. Ketonuria is usually absent, especially in an acute reaction. In prolonged hypoglycemia, however, ketone bodies may be present. Epinephrine and possibly ACTH release caused by hypoglycemia causes an increased release of free fatty acids from adipose tissue, and the oxidation of these is responsible for the increased ketone production. Ketonuria in the absence of glycosuria is therefore not a contraindication to the diagnosis of hypoglycemia. Determination of the blood sugar level is an easy procedure, and when reasonably possible, especially in hospitalized patients, blood should be drawn before treatment is given. If the blood level is below 50 mg. per 100 ml., the diagnosis may be considered proved, especially when the administration of carbohydrates cures the symptoms. Difficulty may arise when the symptoms have been present for a matter of hours and when carbohydrate has been given before the patient has been seen. In these cases, the blood sugar may be in the low normal range, or even higher, but because of the initial severity of the reaction, the symptoms
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and signs have not cleared rapidly. The history in these instances, if obtainable, is important. A thorough examination, possibly including a lumbar puncture, should be made to exclude other possible diagnoses. Often a definite diagnosis can be made only in retrospect when, after maintenance of a normal blood sugar, the patient recovers completely after a period of up to 24 hours or even longer in very severe cases.
Treatment of HypogJycemia The administration of rapidly absorbable carbohydrate is the essential part of all treatment programs. Ten grams of carbohydrate, such as orange juice (100 ml.) or candy, taken orally, is often sufficient. Coca-Cola syrup (a 50 per cent carbohydrate) is good because of the small volume necessary and because it is less nauseating than concentrated cane sugar or glucose solutions. Corn syrup (75 per cent carbohydrate) is also useful. In mild reactions, there is usually no difficulty in giving the carbohydrate orally. In more severe conditions, 20 to 30 grams of carbohydrate may be necessary, and this may be administered by several different techniques. If a patient is uncooperative and has gag and swallowing reflexes, small amounts of concentrated carbohydrates can be poured into the mouth and swallowing encouraged by stroking the throat in a downward direction. In unconscious patients it is sometimes possible to pass a stomach tube. Concentrated solutions are again advisable since the risk of vomiting is reduced by using small volumes. Warm solutions also help to prevent this complication. In all cases, hypoglycemia must be terminated as soon as possible. In unconscious or uncooperative patients parenteral therapy is best; 30 to 50 ml. of a 50 per cent dextrose solution given intravenously will often produce dramatic results. In prolonged hypoglycemia, however, the recovery time will not be rapid although there should be an observable lightening of unconsciousness after the injection is complete. Intravenous therapy requires a quiet, controllable patient with good veins. If these conditions do not apply subcutaneous glucagon (1 to 2 mg.) or epinephrine (0.5 ml. of 1/1000 solution) will cause a sufficient increase in the blood sugar to allow the patient to become rational and cooperative. Glucagon acts by mobilizing liver glycogen, as does epinephrine, which also mobilizes muscle glycogen. With both these forms of treatment an improvement is usually noticed after 10 to 20 minutes. There is a slight risk of producing cardiac arrhythmias when epinephrine is used. No toxic effects have been reported when glucagon is given in the above dose range. In very rare cases, the liver glycogen may be depleted during hypoglycemia, so that glucagon would be of no benefit. If there is no response 20 minutes after the injection, this possibility should be considered, especially in cachectic patients. The hyperglycemic effect of both glucagon and epinephrine is transient and supplementary carbohy-
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drate must be given as soon as the patient is cooperative, to prevent a relapse into hypoglycemia. When recovery is slow, the blood sugar should be checked at frequent intervals to ensure that it remains at normal or, preferably, slightly hyperglycemic levels. This is particularly important when, by accident or design, an overdose of insulin has been given. These patients should receive a constant infusion of 10 per cent dextrose solution to maintain their blood sugar. Finally, an effort should be made to determine the cause of the reaction, and when necessary the insulin dose and diet should be appropriately adjusted. In very severe hypoglycemic reactions, further insulin should be withheld until the blood sugars indicate that it is again necessary.
Prevention of Hypoglycemia The first responsibility in the prevention of hypoglycemia reactions lies with the attending physician. Since the administered insulin is absorbed at a more or less constant rate, the dose and type should be adjusted to produce maximum activity at the times of the major meals. Snacks of between 10 and 15 grams of carbohydrate between meals are of value in "taking up the slack" which develops at these times. This is especially important at bed time. Education of the patient is probably the most important factor in the prevention of hypoglycemic reactions. The patient should be very familiar with the conditions that are likely to cause a reaction, and also with the times at which they are most likely to develop. An awareness of the many and varied symptoms of hypoglycemia is essential. Many diabetics learn by their experiences, and new diabetics should be encouraged to look at each reaction retrospectively, so that they will be able to detect one earlier the next time. It is wise to tell intelligent and reliable patients that unfamiliar peculiar sensations should be considered to be a reaction until proved otherwise. They should be encouraged to test their urine often, and thus be able to detect at an early stage the necessity for a reduction in their insulin dose. Unaccustomed or strenuous physical activity may cause a rapid fall in blood sugar and should be taken into consideration by all patients receiving insulin. The two methods for dealing with this are (i) an increase in the carbohydrate in the diet just before and during the period of activity and (ii) a reduction in the dose of insulin covering the period of anticipated activity. Unless the exercise is very strenuous or guaranteeable, it is probably best to compensate for it by taking extra lO-gram carbohydrate snacks at one- or two-hour intervals during it. This is the logical method since extra energy is required during the activity. However, if the exercise is strenuous and prolonged, a reduction in insulin is also necessary or the patient will have to take so much carbohydrate that his efficiency will be
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reduced by the amount of food in his stomach. The size of the reduction in dose is best determined on the basis of the past experience of each patient. Patients receiving insulin should always carry some form of concentrated carbohydrates with them. There should be no exception to this rule. Reactions, especially in children, can develop at unexpected times and in embarrassing situations, and the confusion produced by the patient may have very unfortunate and far-reaching results. In this respect a problem arises with children, in that they will eat their emergency supply when they do not need it. It is important to impress on them the hazards of this practice. Parents should always check that their supplies are adequate. The best emergency reserve is pure glucose tablets since their flavor is not very pleasant, and there is less tendency for them to be eaten except when necessary. Such tablets, however, are difficult to obtain in North America. Identification is very important. All diabetics should make sure that their friends and close associates know of their condition. They should also carry a card, or metal tag, indicating that they take insulin. Many Diabetic Associations, Clinics and other organizations provide cards and discs on which the essential information can be written or inscribed.
Complications of Hypoglycemia The complications of hypo glycemia are primarily those affecting the central nervous system. The brain depends almost entirely on glucose oxidation for its energy requirements so that deprivation of this source produces a block in cerebral function similar to that seen in anoxia. The severity of the changes is dependent on both the degree and duration of the hypoglycemia. The commonest and most transient sequelae are headache, which can be very severe, and vomiting. Although the latter is often preceded by nausea, it is probably central in origin, and both complications are probably secondary to cerebral edema. In reactions in which the patient has been unconscious the recovery time is sometimes prolonged. Children in particular may remain unconscious for 24 hours despite correction of the hypoglycemia. All degrees of cerebral damage can result from prolonged hypoglycemia, ranging from transient mono- and hemiparesis to severe cortical damage with loss of high cerebral function, complete decerebrate rigidity, and, in a few cases, death. When diffuse cortical damage has occurred, the patient remains unconscious for a varying period, and then gradually recovers over a period of weeks or months, though there is often permanent loss of higher faculties and a reduction in intelligence. Frequent hypoglycemic reactions in children can result in permanent loss of intellectual functionY Electroencephalograms in such patients confirm the presence of diffuse cortical damage.
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SPONTANEOUS HYPOGLYCEMIA
In this section, hypoglycemia developing because of endocrine imbalance or abnormal function is considered as well as that due to unusual response to a variety of exogenous agents. Hypoglycemia Due to Insulinomas
The classic form of spontaneous hypoglycemia is caused by insulinsecreting beta cell adenomas of the islets of Langerhans and represents true hyperinsulinism. The incidence of these tumors in autopsy studies is as common as 1 in 234 cases. 23 However, in only 20 per cent of the cases is there actual hypoglycemic activity. The tumors are usually single, although they may be multiple, 3 and occur with equal frequency in all areas of the pancreas, and occasionally outside it. 23 The tumors may be up to 1 or 2 cm. in diameter, are firm, and have a pinkish color. There is a 10 per cent incidence of malignancy in the functioning tumors. Patients suffering from insulinomas present with the symptoms of hypoglycemia. Occasionally, these are not recognized and valuable time is spent investigating the possibility of psychoneuroses. The diagnosis of such tumors is based on finding a blood sugar level below 40 mg. per 100 m!. Such confirmation is most readily obtained by determining the fasting blood sugar. A six-hour glucose tolerance test is of great value in uncertain cases. A diet containing at least 300 grams of carbohydrate per day for three days before the test is essential, and the test may be regarded as positive when the blood sugar falls to markedly hypoglycemic levels in the four- to six-hour period. It is occasionally necessary to subject the patient to more rigorous diagnostic procedures, such as the three-day low-carbohydrate 1200 calorie diet described by Conn, 7 in order to confirm the diagnosis. The tolbutamide test l3 is very useful, but care should be taken to avoid precipitating severe hypoglycemia, which may develop if an insulinoma is present. If the blood sugar falls below 40 mg. per 100 ml. one and a half to three hours after the intramuscular injection of glucagon, a functioning islet cell tumor is almost certainly present. 31 If the technique is available, assay of the plasma insulin may reveal an abnormally high level,42 but Steinke et al,39 found a poor correlation between the plasma insulin activity and the known tumor activity. The only satisfactory treatment of this condition is surgical excision of the tumor. Care both before and during the operation is necessary to prevent hypoglycemia. The intravenous infusion of 10 per cent dextrose in water and the administration of 100 mg. of cortisone acetate intramuscularly one to two hours before operation have been found to be adequate. l l Complete mobilization and palpation of the pancreas is essential in the detection of all tumors. When no tumor can be found, partial pancreatectomy may be necessary. If the hypoglycemia persists, dexamethazone
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0.75 mg. four times a day and glucagon 1.0 mg. twice a day subcutaneously have been found to help in a few cases. 28
HypogJycemia Due to Nonpancreatic Tumors A great variety of tumors other than insulinomas have hypoglycemic potential, and as this property becomes more widely recognized the variety increases. It is important to note that the hypoglycemic action is due to the primary tumor activity, and is not the result of endocrine imbalance due to secondary spread. In a recent survey Samols36 listed the tumors known to be associated with hypoglycemia, as follows: Mesenchymal Fibrosarcoma Mesothelioma Fibroma Peritoneal myxoma
Epithelial tumors of the liver Carcinoma Cholangioma
Adrenal Adenoma Carcinoma Cecum Carcinoma
Other "hypoglycemic" tumors include bronchogenic carcinoma,41 perineal hemangiopericytoma38 and Wilms' tumor.29 The mechanism by which these tumors exert their hypoglycemic effect probably varies according to the type. The concept that the tumors consume more glucose than they release 7 is supported by the case reported by Landau et al. 27 in a patient with a hepatoma. On the other hand, there are several reportsl. 2. 34 of nonpancreatic tumors which secrete insulin or an insulin-like material. Samols concluded that "non islet cell tumors probably cause hypoglycemia by increased sensitivity to endogenous insulin, or by producing an insulin-like substance."
HypogJycemia Due to Ethanol Ethanol is a well known but relatively rare cause of hypoglycemia. In a recent review, Freinkel et al.,!· on the basis of their own work and evidence in the literature concluded that (i) hypoglycemia is due to ethanol alone and not to the congeners or additives, (ii) neither chronic alcoholism nor chronic malnutrition is an essential prelude to hypoglycemia, (iii) blood ethanol levels just sufficient to cause mild intoxication may cause hypoglycemia in susceptible individuals. A two- or three-day fast was necessary in normal subjects before ethanol could cause hypoglycemia, and in all cases, glucagon did not correct the hypoglycemia, indicating depletion of liver glycogen. It appeared that primary pancreatic mediation was not a factor, since the blood insulin levels were not altered. Alcohol is therefore a primary exogenous hypoglycemic agent. It causes increased release of catecholamines and serotonin from perfused tissues, and since repletion is not immediate, Freinkel et al. considered that this depletion may be a factor in causing hypoglycemia by disturbing the normal homeostatic mechanisms. Other exogenous agents causing
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hypoglycemia are salicylates, 9 manganese35 and monoamine oxidase inhibitors, which may also act by causing catecholamine depletion. 8 Spontaneous Hypoglycemia Due to Other Causes
Hypoglycemia is a well known complication of endocrine imbalance. It is particularly common in hypoadrenalism, largely as a result of decreased gluconeogenesis, and in hypopituitarism, and may occasionally develop in hypothyroidism. Liver parenchymal disease in any form can lead to hypoglycemia. This is in all cases due to the inability of the organ to release glucose into the circulation secondary to impaired gluconeogenesis or defective glycogen storage. Liver diseases associated with hypoglycemia include glycogen storage disease, cirrhosis, chronic venous congestion, acute fatty atrophy and extensive secondary invasion by carcinoma. Idiopathic Hypoglycemia in Infants
Idiopathic hypo glycemia in infants is uncommon, but must be recognized at an early stage if cerebral damage is to be prevented. In 1956, Cochrane et al. 6 showed that one of the causes of this condition was an abnormal sensitivity to I-leucine, and recent studies indicate that this is the responsible factor in about one-third of the cases. 24 It is familial,6 although the exact mode of inheritance is not yet apparent. Other amino acids, such as I-isoleucine and alpha keto-isocaproic acid have been found to cause hypoglycemia19 but the effect is variable, and these substances have no effect in persons who are not leucine-sensitive. lO In a recent review, Schwartz et aJ.37 concluded that there is general agreement that I-leucine and I-isoleucine and their keto analogues cause hypo glycemia in a large proportion of infants with familial hypoglycemia and that most people are sensitive to the hypoglycemic effect of leucine when it is given in large enough doses. Pretreatment with chlorpropamide increases the hypoglycemic response to leucine in sensitive adults. 14 Many patients suffering from islet cell adenomas have been found to be sensitive to the hypoglycemic effects of leucine, but the sensitivity disappears with the removal of the tumors and is also abolished by prednisone therapy. 37 The mechanism of the hypoglycemic action of leucine is not understood. Increased plasma insulin levels during the hypoglycemic phase in these patients have been reported,43 but leucine has also been found to accentuate the hypoglycemia due to exogenous insulin, suggesting both pancreatic and extrapancreatic activity.37 The treatment of this condition consists of preventing the hypoglycemia by (i) limiting the daily dietary leucine to that essential for normal growth and (ii) giving small carbohydrate supplements about 30 minutes after each meal. Fructose intolerance may also cause hypo glycemia. While the total blood sugar is normal or hyperglycemic, the glucose level may fall as low
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as 10 mg. per 100 ml., with the classic signs of hypoglycemia. Froesch et al. 16 postulated that this condition was due to a deficiency of liver aldolase, and this was subsequently confirmed. 20 , 33 The only satisfactory treatment involves the complete removal from the diet of foods containing fructose. Other known causes of idiopathic hypoglycemia in infants include (i) adrenal insufficiency, (ii) panhypopituitarism, (iii) glycogen storage disease, (iv) hypothyroidism, (v) solitary islet cell adenomas, (vi) congenital galactosemia and (vii) maternal diabetes. 32 Reactive Hypoglycemia
A reactive form of intermittent hypoglycemia is sometimes seen following gastric surgery. In these patients the rapid passage of food into and absorption from the small intestine cause transient hyperglycemia. The islet tissue responds to cover the hyperglycemia but, because it is not sustained, overcompensation results, and hypoglycemia develops half an hour to three hours after the meal. The fall in blood sugar, however, is also transient and leads to nothing more than discomfort from mild symptoms. The condition is best treated by diets containing reduced amounts of carbohydrate (100 to 150 grams) and increased protein (100 grams or more). Smaller main meals and between-meal snacks also help. Functional Hypoglycemia
Functional hypoglycemia is a rather ill-defined and poorly understood condition. The blood sugars rarely fall below 40 mg. per 100 ml., and unconsciousness never develops. The patients often show signs of varying degrees of anxiety states and autonomic nervous system imbalance. The diagnosis is usually made on the result of a glucose tolerance test, in which the blood sugar falls to 40 to 50 mg. per 100 ml. in two to three hoursY Treatment consists of a diet in which 25 per cent of the calories are provided by carbohydrates, 25 per cent by protein and 50 per cent by fat, and psychiatric advice. Factitious Hypoglycemia
Factitious hypo glycemia is a very rare condition and is usually encountered in mentally deranged or psychopathic individuals. If this condition is suspected, the patient should be very carefully examined for injection marks, and great care should be taken to eliminate any possible supplies of insulin and the means of administering it. A closely supervised six-hour glucose tolerance test will usually rule out "endogenous" hypoglycemia in these patients.
SUMMARY Hypoglycemia is still the greatest hazard of insulin therapy in diabetes
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mellitus. The warning symptoms of it are protean and may, especially in diabetics of long duration, become hard to detect. The signs of hypoglycemia reflect the degree of disturbance of cerebral metabolism, the higher centers being among the first affected. The diagnosis is usually easy, but, when possible, should be confirmed by urine and blood sugar determinations. Treatment consists of restoring the blood sugar to normal by the most practicable means as soon as possible. The complications of hypoglycemia are the ones resulting from cerebral damage. Education is a very important factor in its prevention. Spontaneous hypoglycemia may develop because of a wide range of causes. These include beta cell adenomas of the islets of Langerhans (true hyperinsulinism), various types of neoplasms, abnormal sensitivity to exogenous agents including alcohol and leucine, endocrine imbalance resulting from impaired function of the pituitary, thyroid or adrenal glands, impaired liver function, altered intestinal absorption secondary to gastric surgery, and functional hypoglycemia.
REFERENCES 1. August, J. T. and Hiatt, H. H.: Severe hypoglycemia secondary to a nonpancreatic fibrosarcoma with insulin activity. New England J. Med. 258: 17, 1958. 2. Boshall, B. R., Kirschenfeld, J. J. and Soteres, P. S.: Extrapancreatic insulinsecreting tumor. New England J. Med. 270: 338,1964. 3. Breidahl, H. D., Priestley, J. T. and Rynearson, E. H.: Clinical aspects of hyperinsulinism. J.A.M.A. 160: 198, 1956. 4. Brit. Med. J. Editorial. Hypoglycaemia from sulphonylureas. Brit. Med. J. 5389: 996,1964. 5. Broberger, D. and Zellerstrom, R.: Hypoglycemia with an inability to increase epinephrine secretion in insulin-induced hypoglycemia. J. Pediat. 59: 215, 1961. 6. Cochrane, W. A., Payne, W. W., Simpkins, M. J. and Woolf, L. 1.: Familial hypoglycemia precipitated by amino acids. J. Clin. Invest. 35: 411, 1956. 7. Conn, J. W. and Seltzer, H. S.: Spontaneous hypoglycemia. Am. J. Med. 19: 460, 1955. 8. Cooper, A. J. and Keddie, K. M. J.: Hypotensive collapse and hypoglycaemia after Mebanazine, a monoamine oxidase inhibitor. Lancet 1: 1133, 1964. 9. Cotton, E. K. and Fahlberg, V. 1.: Hypoglycemia with salicylate poisoning: A report of two cases. Amer. J. Dis. Child. 108: 171,1964. 10. Di George, A. M. and Auerbach, V. H.: Leucine-induced hypoglycemia; a review, and speculation. Amer. J. Med. Sci. 240: 792, 1960. 11. Duncan, G. G.: In Duncan, G. G. (ed.): Diseases of Metabolism, 5th ed. Philadelphia, W. B. Saunders Co., 1964, pp. 888-911. 12. Egeli, E. S. and Berkman, R.: Action of hypoglycemia on coronary insufficiency, and mechanism of E.C.G. alterations. Am. Heart J. 59: 527, 1960. 13. Fajans, S. S. and Conn, J. W.: An intravenous tolbutamide test as an adjunct in the diagnosis of functioning pancreatic islet cell adenomas. J. Lab. & Clin. Med. 54: 811,1959. 14. Fajans, S. S., Power, L., Gwinup, G. W., Knopf, R. F. and Conn, J. W.: Studies on the mechanism of leucine hypoglycemia. J. Lab. & Clin. Med. 56: 810, 1960. 15. Freinkel, N., Singer, D. L., Arky, R. A., Bleicher, S. L., Anderson, J. B. and Silbert, C. K.: Alcohol hypoglycemia. 1. Carbohydrate metabolism in patients with clinical alcohol hypoglycemia, and the experimental reproduction of the syndrome with pure ethanol. J. Clin. Invest. 42: 1112, 1963. 16. Froesch, E. R., Prader, A., Wolf, H. P. and Labhart, A.: Hereditary fructose intolerance. Helvet. paediat. acta 14: 99, 1959.
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17. Gardner, L. I. and Reyersbach, G. C.: Brain damage in the juvenile diabetic patient associated with insulin hypoglycemia. Pediatrics 7: 210, 1951. 18. Greenblat, M., Murray, J. and Root, H. F.: Electroencephalographic studies in diabetes mellitus. New England J. Med. 234: 119, 1946. 19. Grumbach, M. M. and Kaplan, S. L.: Amino acid and alpha keto acid induced hyperinsulinism in the leucine sensitive type of infantile and childhood hypoglycemia. J. Pediat. 57: 346, 1960. 20. Hers, H. G.: Recent developments in the biochemistry of glycogen storage disease and of fructose intolerance. Chemisch. Wchnsb. 57: 437, 1961. 21. Himwich, H. E.: Brain Metabolism and Cerebral Disorders. Baltimore, Waverly Press, Inc., 1951. 22. Hollander, W., Judson, W. E. and Stone, R. W.: Cardiovascular and respiratory responses to infusions of hypertonic saline in patients with or without congestive heart failure. Proc. New England Cardiovasc. Soc. 12: 21, 1953-1954. 23. Howard, J. M., Moss, N. H. and Rhoads, J. E.: Collective review: Hyperinsulinism and islet cell tumors of the pancreas. Surg. Gynec. & Obst. 90: 417, 1950. 24. Hsia, D. Y.: Leucine-induced hypoglycaemia. In Duncan, G. G. (ed.): Diseases of Metabolism. 5th ed. Philadelphia, W. B. Saunders Co., 1964, pp. 339-441. 25. Joslin, E. P.: The critical period of hypoglycemia in undernutrition. M. CLIN. NORTH AMERICA 4: 1723,1921. 26. Kedes, L. H. and Field, J. B.: Hypothermia; a clue to hypoglycemia. New England J. Med. 271: 785,1964. 27. Landau, B. R., Wills, N., Craig, J. W., Leonards, J. R. and Moriwaki, T.:Mechanism of hepatoma-induced hypoglycemia. Cancer 15: 1188, 1962. 28. Leibel, B. S.: Personal communication. 29. Loutfi, A. H., Mehrez, 1., Shabender, S. and Abdine, F. H.: Hypoglycemia with Wilms' tumor. Arch. Dis. Child. 39: 197, 1964. 30. Marble, A.: Treatment of Diabetes Mellitus. 10th ed. Philadelphia, Lea & Febiger, 1959, p. 314. 31. Marks, V.: Response of glucagon by subjects with hyperinsulinism from islet cell tumours. Brit. Med. J. 1: 1539, 1960. 32. McQuarrie, 1.: Idiopathic spontaneous hypoglycemia occurring in infants: Clinical significance of the problem, and treatment. Am. J. Dis. Child. 87: 399, 1954. 33. Nikkila, E. A., Somersalo, 0., Pitkanen, E. and Perheentupa, J.: Hereditary fructose intolerance, an inborn deficiency of liver aldolase complex. Metabolism 11: 727,1962. 34. Oleesky, S., Bailey, 1., Samols, E. and Bilkus, D.: A fibrosarcoma with hypoglycaemic and high serum insulin level. Lancet 7252: 378, 1962. 35. Rubenstein, A. H., Levin, N. W. and Elliott, G. A.: Manganese-induced hypoglycaemia. Lancet 7270: 1348, 1962. 36. Samols, E.: Hypoglycemia in neoplasia. Postgrad. Med. 39: 634, 1963. 37. Schwartz, T. B., Bowyer, A. and Hanashiro, P.: The phenomenon of leucine sensitivity. M. CLIN. NORTH AMERICA 47: 219,1963. 38. Simon, R. and Greene, R. C.: Perineal hemangiopericytoma. A case associated with hypoglycemia. J.A.M.A. 189: 155, 1964. 39. Steinke, J., Soeldner, J. S. and Renold, A. E.: Measurement of small quantities of insulin-like activity with rat adipose tissue. IV. Serum insulin-like activity and tumor insulin content in patients with functioning islet cell tumors. J. Clin. Invest. 42: 1322, 1963. 40. Sussman, K. E., Crout, R. and Marble, A.: Failure of warning in insulin-induced hypoglycaemic reactions. Diabetes 12: 38, 1963. 41. Thorn, G. W. and Castieman, B.: Hypoglycemia in a patient with diabetes mellitus. New England J. Med. 268: 1129, 1963. 42. Yallow, R. A. and Berson, S. A.: Immunoassay of plasma insulin in man. Diabetes 10: 339, 1961. 43. Yallow, R. A. and Berson, S. A.: Immunoassay of endogenous plasma insulin in man. J. Clin. Invest. 39: 1157, 1960. Toronto General Hospital Toronto 2, Ontario, Canada
K. GORMAN, M.D., PH.D.*
HYPOGLYCEMIA
The lower limit of the normal "true" fasting blood sugar is 60 mg. per 100 ml.; by definition, anything below that level represents hypoglycemia. However, by usage "hypoglycemia" has become synonymous with "hypoglycemic" reaction, which is the term used to cover the complex of symptoms and signs which develop when the blood sugar falls to abnormally low levels. The condition can be subdivided into two main categories, (i) that due to the commonly used "therapeutic" hypoglycemic agents, and (ii) spontaneous hypoglycemia and that due to idiosyncratic reaction to drugs and other substances. The major emphasis in this paper will be on the hypoglycemia that occurs as a complication of the treatment of diabetes mellitus. Hypoglycemia as a Complication of the Treatment of Diabetes Mellitus
Before the discovery of insulin, the diagnosis of hypoglycemia was a rarity; the condition was recognized only in diabetics being treated by undernutrition. 25 Since 1922, the condition has become common and still remains the greatest hazard of insulin therapy. The resultant familiarity with the symptoms has, however, allowed hypoglycemia to be recognized in many diseases unrelated to diabetes mellitus. Causes of Hypoglycemia in Diabetes
Insulin therapy is the commonest cause of hypoglycemia in diabetics. The susceptibility to insulin reactions and the time of their onset are influenced by many factors. Reactions due to regular insulin in the normal dose range occur approximately two to six hours after injection. Where large doses of highly concentrated (e.g., 500 units/ml.) regular insulin are used, as in insulin resistance, the action is more prolonged, and reactions can occur at any time of the day. Reactions due to the intermediate-action insulins (N.P.H. and lente) are commonest in the afternoon and evening,
* Assistant
Resident in Medicine, Toronto General Hospital, Toronto, Ontario, Canada. Formerly, Fellow in Medicine, Joslin Clinic, Boston, Massachusetts
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whereas those due to the long-acting varieties (protamine zinc and ultralente) occur at night or in the early morning. The omission of a meal, or unaccustomed exercise will help to precipitate a reaction at any time. Hypoglycemia is being recognized more often in patients being treated with the oral hypoglycemic agents. It was initially thought that these drugs could not cause frank hypoglycemia in diabetics. However, one report4 cites an incidence of reactions in as many as 6 per cent of such patients, and this diagnosis should be kept in mind as an explanation of unusual behavior, or stroke-like states in these people. Symptoms
The blood sugar level at which a hypoglycemic reaction develops is, within limits, variable, and the severity of the reaction is not always proportional to the degree of hypoglycemia. Adults tend to experience symptoms earlier than do children. In the adults, a true blood sugar of 40 mg. per 100 m!. can cause gross confusion, whereas children can behave quite normally with values considerably below this. However, a sudden change from rest to activity in a child in this state may rapidly precipitate the overt signs of hypoglycemia. In both adults and children, a rapid fall in the blood sugar usually produces more severe symptoms, and these may occur in adults even when the blood sugar changes rapidly from hyper- to normoglycemic levels. 30 In contrast, the awareness of symptoms is reduced by treatment with sedatives and monoamine oxidase inhibitors. 8 As a rule, the intermediate and long-acting insulins cause a more gradual onset of symptoms than do the rapidly acting varieties. The early symptoms of hypoglycemia reflect the central effects of the low blood sugar. Himwich21 has reported that these can be divided into five degrees, based on the metabolic requirements of the different areas of the brain. The phylogenetically youngest areas, the cerebral cortex and parts of the cerebellum, had the highest metabolic rates and were the first to suffer, whereas the medulla oblongata, the oldest area and that with the lowest energy requirements, was the last to show impairment. The symptom complexes which vary from one patient to another, and also in the same patient, can be considered under four main headings: 1. Symptoms due to the effects of hypoglycemia on the autonomic nervous system
a. Profuse sweating, even on a cold day b. Hunger c. Paresthesias of the lips and fingers d. Pallor e. Palpitations f. A fine tremor 11. Symptoms due to the effects of hypoglycemia on the central nervous system a. Blurring of vision and diplopia b. Headaches c. Spastic character in movements, especially in the legs d. Lights appearing to have a diffuse glare, especially at night e. Slow reaction time, e.g., when driving or participating in athletic activities f. Frequent and uncontrolled yawning
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Ill. Psychic changes due to hypoglycemia
a. Depression and irritability b. Drowsiness in the normal waking hours and inability to sleep at night c. An unaccustomed inability to concentrate on or comprehend a problem IV. Symptoms due to the effects of hypoglycemia on the muscular system a. Weakness and easy fatigability during heavy physical activity
A patient may experience some or even all of these symptoms during a hypoglycemic reaction. Signs of Hypoglycemia The symptoms mentioned above are experienced in the early stages of hypoglycemia, when the patient is still fully conscious and cooperative. If these are not recognized and the reaction becomes more severe, signs, rather than symptoms, become the clue to diagnosis, since, with the depression of cerebral function, the patient is unable to describe his sensations. The signs which develop are essentially physical manifestations of the symptoms and are not infrequently noticed by casual observers before the patient is aware of any change. When undisturbed, the patient may be unusually quiet and withdrawn, but slight excitement can produce violent activity. Tachycardia is common, as are ventricular premature beats, and electrocardiographic changes have been reported. These consist of S.T. depression in the standard limb and lateral chest leads. Hypoglycemia has been said to cause angina pectoris but has been absent in experimental studies. 12 . 22 Hypoglycemia is a cause of hypokalemia, and it is probable that the E.C.G. changes are secondary to this, since the prior administration of potassium prevents them. 12 Hypothermia is probably commoner in hypo glycemia than is generally recognized, and in some cases it has been an aid to the diagnosis. 26 Involuntary twitching is common, and the patient often manifests sensory aphasia, apraxia and emotionallability. Choreiform and athetoid movements and clonic or tonic seizures may develop. Transient mono- and hemiplegias can occur, particularly in patients suffering from cerebral arteriosclerotic vascular disease. Some patients become frankly psychotic; it has not been established whether there is, in them, an underlying psychiatric disorder which has simply been revealed by the hypoglycemia. Hysteria, catatonia and dementia have been observed. 30 Children who are prone to convulsive reactions have in some cases been found to have abnormal electroencephalograms suggestive of epileptic activity;18 some of these patients have been helped by anticonvulsant drugs. As the hypoglycemia progresses and the patient becomes unconscious, sphincter control may be lost, with consequent involuntary micturition and defecation. At this stage the patient cannot be roused by painful stimuli, the pupils are dilated but react to light, the deep tendon reflexes may be absent, and a Babinski sign is present. It is not uncommon to find
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bizarre neurological signs, with absent or unpaired reflexes on one side and a Babinski response on the other. If the hypoglycemia has been sufficiently severe and prolonged, a completely decerebrate picture will develop. Reactions Without Warning
Diabetic patients on insulin therapy have often complained that hypoglycemic reactions develop without any warning symptoms. This complaint is commonest when the diabetes is of greater than 10 years' duration,30 and its frequency appears to be increasing. 40 The condition appears to be due to a lack of sympathetic response to hypoglycemia5 , 40 which is not necessarily associated with any obvious sensory neuropathy. The situation created by these "reactions without warning" is very distressing to the patient. Two therapeutic approaches are necessary: (i) reorganization of the therapeutic regimen to minimize the risk of hypoglycemia and (ii) re-education of the patient. The patient must constantly be on the alert for any unusual symptoms and should follow the maxim that any peculiar sensation is a reaction until proved otherwise. It is most important for him to look for parasympathetic and cerebral signs. If in doubt, he should take 5 to 10 grams of carbohydrates and watch himself closely. It is unlikely that treatment with ephedrin sulfate will have any beneficial effect. Diagnosis of Hypoglycemic Reaction If hypo glycemia is suspected, the urine should be tested. If the first sample contains sugar, another specimen obtained soon afterwards should be tested. If hypoglycemia exists, the second sample will be sugar-free, or at least it will contain much less sugar than the first sample, which may contain urine secreted during an earlier period of hyperglycemia, unless the patient cannot void completely because of a "neurogenic" bladder. Ketonuria is usually absent, especially in an acute reaction. In prolonged hypoglycemia, however, ketone bodies may be present. Epinephrine and possibly ACTH release caused by hypoglycemia causes an increased release of free fatty acids from adipose tissue, and the oxidation of these is responsible for the increased ketone production. Ketonuria in the absence of glycosuria is therefore not a contraindication to the diagnosis of hypoglycemia. Determination of the blood sugar level is an easy procedure, and when reasonably possible, especially in hospitalized patients, blood should be drawn before treatment is given. If the blood level is below 50 mg. per 100 ml., the diagnosis may be considered proved, especially when the administration of carbohydrates cures the symptoms. Difficulty may arise when the symptoms have been present for a matter of hours and when carbohydrate has been given before the patient has been seen. In these cases, the blood sugar may be in the low normal range, or even higher, but because of the initial severity of the reaction, the symptoms
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and signs have not cleared rapidly. The history in these instances, if obtainable, is important. A thorough examination, possibly including a lumbar puncture, should be made to exclude other possible diagnoses. Often a definite diagnosis can be made only in retrospect when, after maintenance of a normal blood sugar, the patient recovers completely after a period of up to 24 hours or even longer in very severe cases.
Treatment of HypogJycemia The administration of rapidly absorbable carbohydrate is the essential part of all treatment programs. Ten grams of carbohydrate, such as orange juice (100 ml.) or candy, taken orally, is often sufficient. Coca-Cola syrup (a 50 per cent carbohydrate) is good because of the small volume necessary and because it is less nauseating than concentrated cane sugar or glucose solutions. Corn syrup (75 per cent carbohydrate) is also useful. In mild reactions, there is usually no difficulty in giving the carbohydrate orally. In more severe conditions, 20 to 30 grams of carbohydrate may be necessary, and this may be administered by several different techniques. If a patient is uncooperative and has gag and swallowing reflexes, small amounts of concentrated carbohydrates can be poured into the mouth and swallowing encouraged by stroking the throat in a downward direction. In unconscious patients it is sometimes possible to pass a stomach tube. Concentrated solutions are again advisable since the risk of vomiting is reduced by using small volumes. Warm solutions also help to prevent this complication. In all cases, hypoglycemia must be terminated as soon as possible. In unconscious or uncooperative patients parenteral therapy is best; 30 to 50 ml. of a 50 per cent dextrose solution given intravenously will often produce dramatic results. In prolonged hypoglycemia, however, the recovery time will not be rapid although there should be an observable lightening of unconsciousness after the injection is complete. Intravenous therapy requires a quiet, controllable patient with good veins. If these conditions do not apply subcutaneous glucagon (1 to 2 mg.) or epinephrine (0.5 ml. of 1/1000 solution) will cause a sufficient increase in the blood sugar to allow the patient to become rational and cooperative. Glucagon acts by mobilizing liver glycogen, as does epinephrine, which also mobilizes muscle glycogen. With both these forms of treatment an improvement is usually noticed after 10 to 20 minutes. There is a slight risk of producing cardiac arrhythmias when epinephrine is used. No toxic effects have been reported when glucagon is given in the above dose range. In very rare cases, the liver glycogen may be depleted during hypoglycemia, so that glucagon would be of no benefit. If there is no response 20 minutes after the injection, this possibility should be considered, especially in cachectic patients. The hyperglycemic effect of both glucagon and epinephrine is transient and supplementary carbohy-
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drate must be given as soon as the patient is cooperative, to prevent a relapse into hypoglycemia. When recovery is slow, the blood sugar should be checked at frequent intervals to ensure that it remains at normal or, preferably, slightly hyperglycemic levels. This is particularly important when, by accident or design, an overdose of insulin has been given. These patients should receive a constant infusion of 10 per cent dextrose solution to maintain their blood sugar. Finally, an effort should be made to determine the cause of the reaction, and when necessary the insulin dose and diet should be appropriately adjusted. In very severe hypoglycemic reactions, further insulin should be withheld until the blood sugars indicate that it is again necessary.
Prevention of Hypoglycemia The first responsibility in the prevention of hypoglycemia reactions lies with the attending physician. Since the administered insulin is absorbed at a more or less constant rate, the dose and type should be adjusted to produce maximum activity at the times of the major meals. Snacks of between 10 and 15 grams of carbohydrate between meals are of value in "taking up the slack" which develops at these times. This is especially important at bed time. Education of the patient is probably the most important factor in the prevention of hypoglycemic reactions. The patient should be very familiar with the conditions that are likely to cause a reaction, and also with the times at which they are most likely to develop. An awareness of the many and varied symptoms of hypoglycemia is essential. Many diabetics learn by their experiences, and new diabetics should be encouraged to look at each reaction retrospectively, so that they will be able to detect one earlier the next time. It is wise to tell intelligent and reliable patients that unfamiliar peculiar sensations should be considered to be a reaction until proved otherwise. They should be encouraged to test their urine often, and thus be able to detect at an early stage the necessity for a reduction in their insulin dose. Unaccustomed or strenuous physical activity may cause a rapid fall in blood sugar and should be taken into consideration by all patients receiving insulin. The two methods for dealing with this are (i) an increase in the carbohydrate in the diet just before and during the period of activity and (ii) a reduction in the dose of insulin covering the period of anticipated activity. Unless the exercise is very strenuous or guaranteeable, it is probably best to compensate for it by taking extra lO-gram carbohydrate snacks at one- or two-hour intervals during it. This is the logical method since extra energy is required during the activity. However, if the exercise is strenuous and prolonged, a reduction in insulin is also necessary or the patient will have to take so much carbohydrate that his efficiency will be
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reduced by the amount of food in his stomach. The size of the reduction in dose is best determined on the basis of the past experience of each patient. Patients receiving insulin should always carry some form of concentrated carbohydrates with them. There should be no exception to this rule. Reactions, especially in children, can develop at unexpected times and in embarrassing situations, and the confusion produced by the patient may have very unfortunate and far-reaching results. In this respect a problem arises with children, in that they will eat their emergency supply when they do not need it. It is important to impress on them the hazards of this practice. Parents should always check that their supplies are adequate. The best emergency reserve is pure glucose tablets since their flavor is not very pleasant, and there is less tendency for them to be eaten except when necessary. Such tablets, however, are difficult to obtain in North America. Identification is very important. All diabetics should make sure that their friends and close associates know of their condition. They should also carry a card, or metal tag, indicating that they take insulin. Many Diabetic Associations, Clinics and other organizations provide cards and discs on which the essential information can be written or inscribed.
Complications of Hypoglycemia The complications of hypo glycemia are primarily those affecting the central nervous system. The brain depends almost entirely on glucose oxidation for its energy requirements so that deprivation of this source produces a block in cerebral function similar to that seen in anoxia. The severity of the changes is dependent on both the degree and duration of the hypoglycemia. The commonest and most transient sequelae are headache, which can be very severe, and vomiting. Although the latter is often preceded by nausea, it is probably central in origin, and both complications are probably secondary to cerebral edema. In reactions in which the patient has been unconscious the recovery time is sometimes prolonged. Children in particular may remain unconscious for 24 hours despite correction of the hypoglycemia. All degrees of cerebral damage can result from prolonged hypoglycemia, ranging from transient mono- and hemiparesis to severe cortical damage with loss of high cerebral function, complete decerebrate rigidity, and, in a few cases, death. When diffuse cortical damage has occurred, the patient remains unconscious for a varying period, and then gradually recovers over a period of weeks or months, though there is often permanent loss of higher faculties and a reduction in intelligence. Frequent hypoglycemic reactions in children can result in permanent loss of intellectual functionY Electroencephalograms in such patients confirm the presence of diffuse cortical damage.
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SPONTANEOUS HYPOGLYCEMIA
In this section, hypoglycemia developing because of endocrine imbalance or abnormal function is considered as well as that due to unusual response to a variety of exogenous agents. Hypoglycemia Due to Insulinomas
The classic form of spontaneous hypoglycemia is caused by insulinsecreting beta cell adenomas of the islets of Langerhans and represents true hyperinsulinism. The incidence of these tumors in autopsy studies is as common as 1 in 234 cases. 23 However, in only 20 per cent of the cases is there actual hypoglycemic activity. The tumors are usually single, although they may be multiple, 3 and occur with equal frequency in all areas of the pancreas, and occasionally outside it. 23 The tumors may be up to 1 or 2 cm. in diameter, are firm, and have a pinkish color. There is a 10 per cent incidence of malignancy in the functioning tumors. Patients suffering from insulinomas present with the symptoms of hypoglycemia. Occasionally, these are not recognized and valuable time is spent investigating the possibility of psychoneuroses. The diagnosis of such tumors is based on finding a blood sugar level below 40 mg. per 100 m!. Such confirmation is most readily obtained by determining the fasting blood sugar. A six-hour glucose tolerance test is of great value in uncertain cases. A diet containing at least 300 grams of carbohydrate per day for three days before the test is essential, and the test may be regarded as positive when the blood sugar falls to markedly hypoglycemic levels in the four- to six-hour period. It is occasionally necessary to subject the patient to more rigorous diagnostic procedures, such as the three-day low-carbohydrate 1200 calorie diet described by Conn, 7 in order to confirm the diagnosis. The tolbutamide test l3 is very useful, but care should be taken to avoid precipitating severe hypoglycemia, which may develop if an insulinoma is present. If the blood sugar falls below 40 mg. per 100 ml. one and a half to three hours after the intramuscular injection of glucagon, a functioning islet cell tumor is almost certainly present. 31 If the technique is available, assay of the plasma insulin may reveal an abnormally high level,42 but Steinke et al,39 found a poor correlation between the plasma insulin activity and the known tumor activity. The only satisfactory treatment of this condition is surgical excision of the tumor. Care both before and during the operation is necessary to prevent hypoglycemia. The intravenous infusion of 10 per cent dextrose in water and the administration of 100 mg. of cortisone acetate intramuscularly one to two hours before operation have been found to be adequate. l l Complete mobilization and palpation of the pancreas is essential in the detection of all tumors. When no tumor can be found, partial pancreatectomy may be necessary. If the hypoglycemia persists, dexamethazone
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0.75 mg. four times a day and glucagon 1.0 mg. twice a day subcutaneously have been found to help in a few cases. 28
HypogJycemia Due to Nonpancreatic Tumors A great variety of tumors other than insulinomas have hypoglycemic potential, and as this property becomes more widely recognized the variety increases. It is important to note that the hypoglycemic action is due to the primary tumor activity, and is not the result of endocrine imbalance due to secondary spread. In a recent survey Samols36 listed the tumors known to be associated with hypoglycemia, as follows: Mesenchymal Fibrosarcoma Mesothelioma Fibroma Peritoneal myxoma
Epithelial tumors of the liver Carcinoma Cholangioma
Adrenal Adenoma Carcinoma Cecum Carcinoma
Other "hypoglycemic" tumors include bronchogenic carcinoma,41 perineal hemangiopericytoma38 and Wilms' tumor.29 The mechanism by which these tumors exert their hypoglycemic effect probably varies according to the type. The concept that the tumors consume more glucose than they release 7 is supported by the case reported by Landau et al. 27 in a patient with a hepatoma. On the other hand, there are several reportsl. 2. 34 of nonpancreatic tumors which secrete insulin or an insulin-like material. Samols concluded that "non islet cell tumors probably cause hypoglycemia by increased sensitivity to endogenous insulin, or by producing an insulin-like substance."
HypogJycemia Due to Ethanol Ethanol is a well known but relatively rare cause of hypoglycemia. In a recent review, Freinkel et al.,!· on the basis of their own work and evidence in the literature concluded that (i) hypoglycemia is due to ethanol alone and not to the congeners or additives, (ii) neither chronic alcoholism nor chronic malnutrition is an essential prelude to hypoglycemia, (iii) blood ethanol levels just sufficient to cause mild intoxication may cause hypoglycemia in susceptible individuals. A two- or three-day fast was necessary in normal subjects before ethanol could cause hypoglycemia, and in all cases, glucagon did not correct the hypoglycemia, indicating depletion of liver glycogen. It appeared that primary pancreatic mediation was not a factor, since the blood insulin levels were not altered. Alcohol is therefore a primary exogenous hypoglycemic agent. It causes increased release of catecholamines and serotonin from perfused tissues, and since repletion is not immediate, Freinkel et al. considered that this depletion may be a factor in causing hypoglycemia by disturbing the normal homeostatic mechanisms. Other exogenous agents causing
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hypoglycemia are salicylates, 9 manganese35 and monoamine oxidase inhibitors, which may also act by causing catecholamine depletion. 8 Spontaneous Hypoglycemia Due to Other Causes
Hypoglycemia is a well known complication of endocrine imbalance. It is particularly common in hypoadrenalism, largely as a result of decreased gluconeogenesis, and in hypopituitarism, and may occasionally develop in hypothyroidism. Liver parenchymal disease in any form can lead to hypoglycemia. This is in all cases due to the inability of the organ to release glucose into the circulation secondary to impaired gluconeogenesis or defective glycogen storage. Liver diseases associated with hypoglycemia include glycogen storage disease, cirrhosis, chronic venous congestion, acute fatty atrophy and extensive secondary invasion by carcinoma. Idiopathic Hypoglycemia in Infants
Idiopathic hypo glycemia in infants is uncommon, but must be recognized at an early stage if cerebral damage is to be prevented. In 1956, Cochrane et al. 6 showed that one of the causes of this condition was an abnormal sensitivity to I-leucine, and recent studies indicate that this is the responsible factor in about one-third of the cases. 24 It is familial,6 although the exact mode of inheritance is not yet apparent. Other amino acids, such as I-isoleucine and alpha keto-isocaproic acid have been found to cause hypoglycemia19 but the effect is variable, and these substances have no effect in persons who are not leucine-sensitive. lO In a recent review, Schwartz et aJ.37 concluded that there is general agreement that I-leucine and I-isoleucine and their keto analogues cause hypo glycemia in a large proportion of infants with familial hypoglycemia and that most people are sensitive to the hypoglycemic effect of leucine when it is given in large enough doses. Pretreatment with chlorpropamide increases the hypoglycemic response to leucine in sensitive adults. 14 Many patients suffering from islet cell adenomas have been found to be sensitive to the hypoglycemic effects of leucine, but the sensitivity disappears with the removal of the tumors and is also abolished by prednisone therapy. 37 The mechanism of the hypoglycemic action of leucine is not understood. Increased plasma insulin levels during the hypoglycemic phase in these patients have been reported,43 but leucine has also been found to accentuate the hypoglycemia due to exogenous insulin, suggesting both pancreatic and extrapancreatic activity.37 The treatment of this condition consists of preventing the hypoglycemia by (i) limiting the daily dietary leucine to that essential for normal growth and (ii) giving small carbohydrate supplements about 30 minutes after each meal. Fructose intolerance may also cause hypo glycemia. While the total blood sugar is normal or hyperglycemic, the glucose level may fall as low
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as 10 mg. per 100 ml., with the classic signs of hypoglycemia. Froesch et al. 16 postulated that this condition was due to a deficiency of liver aldolase, and this was subsequently confirmed. 20 , 33 The only satisfactory treatment involves the complete removal from the diet of foods containing fructose. Other known causes of idiopathic hypoglycemia in infants include (i) adrenal insufficiency, (ii) panhypopituitarism, (iii) glycogen storage disease, (iv) hypothyroidism, (v) solitary islet cell adenomas, (vi) congenital galactosemia and (vii) maternal diabetes. 32 Reactive Hypoglycemia
A reactive form of intermittent hypoglycemia is sometimes seen following gastric surgery. In these patients the rapid passage of food into and absorption from the small intestine cause transient hyperglycemia. The islet tissue responds to cover the hyperglycemia but, because it is not sustained, overcompensation results, and hypoglycemia develops half an hour to three hours after the meal. The fall in blood sugar, however, is also transient and leads to nothing more than discomfort from mild symptoms. The condition is best treated by diets containing reduced amounts of carbohydrate (100 to 150 grams) and increased protein (100 grams or more). Smaller main meals and between-meal snacks also help. Functional Hypoglycemia
Functional hypoglycemia is a rather ill-defined and poorly understood condition. The blood sugars rarely fall below 40 mg. per 100 ml., and unconsciousness never develops. The patients often show signs of varying degrees of anxiety states and autonomic nervous system imbalance. The diagnosis is usually made on the result of a glucose tolerance test, in which the blood sugar falls to 40 to 50 mg. per 100 ml. in two to three hoursY Treatment consists of a diet in which 25 per cent of the calories are provided by carbohydrates, 25 per cent by protein and 50 per cent by fat, and psychiatric advice. Factitious Hypoglycemia
Factitious hypo glycemia is a very rare condition and is usually encountered in mentally deranged or psychopathic individuals. If this condition is suspected, the patient should be very carefully examined for injection marks, and great care should be taken to eliminate any possible supplies of insulin and the means of administering it. A closely supervised six-hour glucose tolerance test will usually rule out "endogenous" hypoglycemia in these patients.
SUMMARY Hypoglycemia is still the greatest hazard of insulin therapy in diabetes
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mellitus. The warning symptoms of it are protean and may, especially in diabetics of long duration, become hard to detect. The signs of hypoglycemia reflect the degree of disturbance of cerebral metabolism, the higher centers being among the first affected. The diagnosis is usually easy, but, when possible, should be confirmed by urine and blood sugar determinations. Treatment consists of restoring the blood sugar to normal by the most practicable means as soon as possible. The complications of hypoglycemia are the ones resulting from cerebral damage. Education is a very important factor in its prevention. Spontaneous hypoglycemia may develop because of a wide range of causes. These include beta cell adenomas of the islets of Langerhans (true hyperinsulinism), various types of neoplasms, abnormal sensitivity to exogenous agents including alcohol and leucine, endocrine imbalance resulting from impaired function of the pituitary, thyroid or adrenal glands, impaired liver function, altered intestinal absorption secondary to gastric surgery, and functional hypoglycemia.
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