Andre Nadeau Functional : Facts and Fancies SUMMARY SOMMAIRE en bas d'un certain When blood decreases below a given Lorsque la glycemie s'abaisse seuil, il y a apparition de sympt6mes de threshold, symptoms of cerebral dysfunction dysfonctionnement cerebral et/ou d'hyperactivite and/or adrenergic hyperactivity appear. If this adrenergique. Lorsque ceci survient apres le repas occurs postprandially in otherwise normal chez une personne par ailleurs normale, un subjects, a diagnosis of reactive or functional diagnostic d'hypoglycemie reactionnelle ou hypoglycemia may be proposed. However, fonctionnelle peut etre avance. Neanmoins, ces symptomes ne sont pas tellement specifiques, et ils symptoms are not specific, and they these devraient coincider avec des valeurs glycemiques should coindde with low blood glucose values basses et se corriger rapidement suite a l'ingestion and be rapidly relieved by glucose ingestion de glucose avant de porter le diagnostic before a diagnosis of hypoglycemia is d'hypoglycemie. L'epreuve d'hyperglycemie confirmed. The oral , provoquee par voie orale souvent utilisee dans often used in the evaluation of such patients, l'evaluation de ces patients peut egalement donner des r6sultats trompeurs, car beaucoup de sujets also may give misleading results, because normaux presentent des glycemies en bas de la many normal subjects have glucose values "normale" lors de ce test. Ceci explique sans doute below the 'normal' range during the test. This pourquoi le diagnostic d'hypoglycemie fonctionnelle may explain why functional hypoglycemia has a ete surutilise depuis plusieurs annees, amenant la probably been overdiagnosed during the last description du syndrome de non-hypoglyc6mie qui consiste a attribuer par erreur les symptomes a de years, giving rise to a description of several l'hypoglycemie, soit par le patient lui-meme ou the syndrome of non-hypoglycemia, in which meme par son medecin. Neanmoins, I'hypoglycemie the patient's symptoms are falsely attributed fonctionnelle existe et peut etre amelioree par un to hypoglycemia, either by himself or by his traitement approprie. . Nevertheless, functional hypoglycemia exists and can be improved by proper management. (Can Fam Physician 1984; 30:1333-1335)

Dr. Nadeau is an associate the pathological counterpart to dia- glucose in the range of 70-100 mg/dl professor of at Laval betes mellitus. Many years later, the is considered normal,3 more than five University, and Director, concept of hypoglycemia evolved into percent of normal subjects are ex- Laboratoires de Recherche en a broad classification encompassing pected to have values outside these Endocrinologie et Metabolisme, Le many different and unrelated patholog- limits. Furthermore, to be considered Centre Hospitalier de l'Universite ical entities.2 This is not really surpris- part of a disease entity, low blood glu- Laval, Ste-Foy. Reprint requests to: ing, because blood glucose is normally cose concentration should be asso- Le Centre Hospitalier de controlled by many biochemical fac- ciated with disturbance in some body l'Universite Laval, 2705, Laurier tors (enzymes) and physiological fac- functions. This is particularly impor- Blvd., Ste-Foy, PQ. GlV 4G2. tors (hormones) located in many dif- tant if glucose is measured after a glu- ferent organs. Various inherited or cose challenge, such as that done dur- acquired pathological processes can ing an oral glucose tolerance test. HORTLY AFTER the discovery of alter these factors. Studies conducted in large population in 1924, Harris1 reported By definition, hypoglycemia is a samples2' 4 have shown that many nor- five nondiabetic subjects with symp- biochemical abnormality (i.e., a blood mal subjects may have plasma glucose toms similar to those occurring during glucose value below the normal values below 50 mg/dl without any an insulin reaction in insulin-treated range). Unfortunately, defining the symptoms. On the other hand, other diabetic patients. He was probably the normal range of blood or plasma glu- people may experience typical symp- first to postulate that hyperinsulinism cose is not as simple as it may seem. toms with values in the 50-70 mg/dl or dysinsulinism could well represent While for practical purposes, plasma range and even above 70 mg/dl. Thus, 1333 CAN. FAM. PHYSICIAN Vol. 30: JUNE 1984 diagnosis of reactive or post-prandial tion and then a rapid drop in blood glu- form a five-hour glucose tolerance hypoglycemia depends on more or less cose concentration and a typical hy- test, with blood samples taken at 30- subjective clinical manifestations. poglycemic attack.5 minute intervals after an overnight Although functional hypoglycemia fast. 5' 6 Unfortunately, as noted above, Clinical Manifestations is manifested more specifically by epi- many asymptomatic normal subjects Of Hypoglycemia sodes of the symptoms mentioned may have glucose values below the so- The clinical manifestations of hy- above, sometimes patients mainly called normal range; because of this, poglycemia can be grouped under two complain of more chronic disabilities probably many patients with non- headings: those caused by neurogluco- such as progressive , lack of en- hypoglycemia have been misdiag- penia, and those induced by adrenergic ergy, depressed mood or emotional in- nosed by their physician as suffering overactivity. stability. Although it is well known from reactive hypoglycemia. In such Glucose is the major fuel of the that functional hypoglycemia is asso- cases, failure to recognize non- brain. The central nervous system con- ciated with emotional disturbance and hypoglycemia may preclude further tinuously uses glucose and oxygen to personality disorder, it is not clear exploration of alternative diagnoses function. If the supply of glucose whether hypoglycemia is the cause or and treatments, and this should always diminishes, then symptoms of neuro- the consequence of such distur- be kept in mind when a diagnosis of glucopenia appear. Depending on the bances.6 hypoglycemia is proposed. severity of the glucose shortage, sub- jects may experience fatigue, head- Hypoglycemia Vs. Diagnosis Of ache, visual disturbances, faintness, 'Non-Hypoglycemia' Reactive Hypoglycemia difficulty with speech and thinking, Obviously, neither the neurogluco- Proper diagnosis of reactive hypo- confusion and even seizures and coma. penic nor the adrenergic symptoms glycemia (or any other type of hypog- Psychiatric manifestations such as out- mentioned above are specific and ev- lycemia) requires that there is a typical bursts of temper or bizarre behavior erybody has probably experienced symptomatic attack, which is asso- may also occur. 3 5 some of them. For many years, hypo- ciated with a low plasma or blood glu- Activation of the autonomic ner- glycemia has attracted the public cose, and that relief of symptoms is vous system and the ensuing release of press, which is always attentive to the rapid after glucose administration. epinephrine by the adrenal medulla public's desire for information about However, this triad, known as the triad cause the of health matters.2 5 Often, after reading of Whipple, is rarely demonstrated adrenergic overactivity. These symp- a magazine article on the subject, a pa- spontaneously, and provocative tests toms include sweating, , tient will visit me with his own diag- are usually needed.5 Although the ap- tachycardia, shakiness, , ner- nosis of hypoglycemia. In the U.S., propriateness of the oral glucose toler- vousness or .3' 5 the diagnosis of hypoglycemia seems ance test has been challenged,8 it re- Some subjects feel hungry, but nau- to have reached epidemic proportions mains the more standardized approach sea and also may be present. in recent years.7 Looking at this phe- to assess glucose . To be While the neuroglucopenic symp- nomenon, Yager and Young described diagnostic of reactive hypoglycemia, toms usually predominate with the the syndrome of non-hypoglycemia.7 the appearance of symptoms during gradual onset of fasting hypoglycemia, These authors reported their own expe- the test should coincide with the nadir the adrenergic manifestations normally rience with many patients who ac- of plasma glucose. Measurements of predominate with the more rapid onset counted for their symptoms by falsely plasma cortisol and/or epinephrine of postprandial or reactive hypoglyce- attributing them to hypoglycemia. have been used to demonstrate the ac- mia. Nevertheless, both groups of Such a diagnosis has the obvious ad- tivation of the hypothalamic pituitary- symptoms, or either alone, may be ob- vantage of being more socially accept- adrenal axis in response to the central served in reactive hypoglycemia.5 able then a psychologic or otherwise neuroglucopenic stress. However, the With the functional type of reactive stigmatizing condition. Furthermore, significance of these measurements hypoglycemia, the symptoms typically the mere fact of having a medical diag- should be more clearly established be- develop 90 minutes to two hours after nosis for ambiguous and often perplex- fore their general use is advocated. Fi- a meal, most often after breakfast. The ing symptoms can provide some relief nally, although subjects with reactive symptoms are transitory and usually to these subjects. Finally, the more or hypoglycemia may, as a group, differ subside in 15-30 minutes. Convulsions less 'ritual' approach of adhering to a in their plasma insulin curve from nor- and loss of consciousness are unusual, strict diet and/or taking multiple daily mal subjects, abnormalities in the indi- and their presence should always sug- tablets of vitamins as proposed in the vidual pattern of insulin response are gest that other causes of hypogly- public press appears to be an easy way rarely found, with the exception of pa- cemia, particularly , be to cope with symptoms, and fits well tients with diabetic reactive hypogly- sought. Reactive hypoglycemia also with the compulsive habits of most of cemia. Insulin measurements should may be present three to five hours after these people. be limited to special investigation a meal, and appears to be associated Theoretically, the diagnosis of non- only. with a special type of diabetes mellitus hypoglycemia should be easy to make; in which the insulin response to glu- it requires only the demonstration that Treatment Of cose is quantitatively important but de- glucose metabolism is normal and that Reactive layed. This causes abnormally high no relation exists between blood Hypoglycemia blood glucose values during the two to level and the patient's symptoms.7 To Once a diagnosis of reactive hypo- three hours following glucose inges- do this, the usual approach is to per- glycemia has been made, the available 1334 CAN. FAM. PHYSICIAN Vol. 30: JUNE 1984 therapeutic modalities should be dis- reactive hypoglycemia of the diabetic cussed with the patient. type. In those with the functional type Probably the most important aspect of reactive hypoglycemia, an anti- of managing such patients is to give cholinergic drug taken 30 minutes be- them simple but clear and precise ex- fore meals may be beneficial; possibly Beconase planations about their problem. For it diminishes the influence of foods on (beclomethasone dipropionate) those who have experienced the dis- the insulinogenic gastrointestinal hor- tressing symptoms of an acute adrena- mones. When prescribing such drugs, Prescribing Information Indications and clinical uses line discharge, the relationship be- the physician should be aware of the Beconase is indicated for the treatment of perennial and seasonal tween their unpleasant feelings and a fact that reactive hypoglycemia is a allergic unresponsive to conventional treatment Contraindications simple disturbance in blood glucose chronic disorder and that medication Active or quiescent tuberculosis or untreated fungal. bacterial and homeostasis may not be self-evident. viral infections Children under six years of age may be needed for many years. Warnings However, such patients may easily un- In patients previously on high doses of systemic steroids. transfer to Beconase may cause withdrawal symptoms such as tiredness. aches derstand and accept that after a meal, Conclusion and pains. and In severe cases, adrenal insufficiency may occur. necessitating the temporary resumption of systemic steroids. blood glucose normally goes up and Reactive The safety of Beconase in pregnancy has not been established. If then goes down; maintenance of blood hypoglycemia is a condi- used. the expected benefits should be weighed against the potential tion which is not easily diagnosed. The hazard to the fetus. particularly during the first trimester of pregnancy. glucose concentration within a normal Precautions demonstration of typical symptoms as- The replacement of a systemic steroid with Beconase has to be narrow range is controlled by a very gradual and carefully supervised by the physician. The guidelines sociated with low blood glucose is im- under Administration should be followed in all such cases. sophisticated body system that some- Unnecessary administration of drugs during pregnancy is undesirable. perative. Unfortunately, the com- Corticosteroids may mask some signs of infection and new times appears to be hypersensitive, monly used oral glucose tolerance test infections may appear A decreased resistance to localized intection thus reactive hypoglycemia, has been observed during corticosteroid During long-term causing is a very imperfect way of document- therapy pituitary-adrenal function and hematological status should with possibly all the subsequent be periodically assessed Fluorocarbon propellants may behazardous ing reactive hypoglycemia,8 and cau- it they are deliberately abused Inhalation of high concentrations of neuroglucopenic and hyperadrenergic aerosol sprays has brought about cardiovascular toxic effects. and tion should be taken to distinguish even death especially under conditions of hypoxia However. symptoms previously described. Such evidence attests to the relative satety of aerosols when used between hypoglycemia and non- intranasally and with adequate ventilation patients may be reassured by knowing There is an enhanced eftect of corticosteroids on patients with hypoglycemia. and in those with cirrhosis that this response more or less re- Once the diagnosis of functional hy- Acetylsalicylic acid should be used cautiously in conjunction with sembles the situation when the fear corticosteroids in hypoprothrombinemia poglycemia is established, diet therapy Patients should be advised to inform subsequent of the normally experienced at the sight of a prior use of corticosteroids is usually effective, but explanations During Beconase therapy. the possibility of atrophic rhinitis and/or small animal (e.g., a mouse) is exag- and reassurance of the patient are in- pharyngeal candidiasis should be kept in mind gerated to the point of faintness, and Adverse reactions tegral parts of management. Drug ther- No malor side-effects attributable to Beconase have been reported. does not correspond to any serious ill- Occasional sneezing attacks have followed immediately after the use apy should be limited to subjects who of the intranasal aerosol A few patients have complained of burning ness. Along with some improvement sensation and irritation in the nose after Beconase Nasal Inhalation. do not benefit greatly from dietary. When patients are transferred to Beconase frorm a systemic steroid. in the anxiety associated with this par- measures. allergic conditions such as asthma or eczema may be unmasked ticular problem, such detailed explana- Dosage and administration The usual dose for patients of all ages who received no previous tions on the physiopathogenesis of the systemic steroid iS one application 150 mcg of beclomethasone dipropionatel into each nostril three to four times daily. Maximum hypoglycemic attack often permit the References daily dose should not exceed twenty applications in adults and ten applications in children It Beclovent is used concurrently. the patient to detect the initial symptoms 1. Harris S: Hyperinsulinism and dysinsu- maximuiri dose of each aerosol is ten applications in adults and five applications in children Beconase should not be used under six years of his episodes and alleviate them by linism. JAMA 1924; 83:729-733. of age immediately taking a small amount of 2. Hofeldt FD: Reactive hypoglycemia. Since the effect of Beconase depends on its regular use. patients must Metabolism 1975; 24:1193-1208. be instructed to take the nasal inhalations at regular intervals and sugar. not.as with other nasal sprays. as they feel necessary They should 3. Gastineau CF: Is reactive hypoglycemia also be instructed in the correct method. which is to blow the nose. in- then insert the nozzle firmly into the nostril. compress the opposite The patient should then be a clinical entity? Mayo Clin Proc 1983; nostri and actuate the aerosol while inspiring through the nose. with structed that the more specific ap- 58:545-549. the mouth closed RW: The In the presence of excessive nasal mucus secretion or edema of the proach to prevent the hypoglycemic 4. Lev-Ran A, Anderson diag- nasal mucosa. the drug may fail to reach the site of action In such nosis of postprandial hypoglycemia. Dia- cases it is advisable to use a nasal vasoconstrictor for two to three episodes is dietetic; it has long been days prior to Beconase betes 1981; 30:996-999. Careful attention must be given to patients previously treated for recognized that these patients usually 5. Permutt MA: Postprandial hypoglyce- prolonged periods with systemic corticosteroids when transferred to Beconase Initially. Beconase and the systemic corticosteroid must benefit from small and frequent meals mia. Diabetes 1976; 25:719-736. be given concomitantly. while the dose of the latter is gradually 6. Anthony D, Dippe S, Hofeldt FD, et al: decreased The usual rate of withdrawal of the systemic steroid is the and a low diet (refined equivalent of 2 5 mg of prednisone every four days it the patient is should be totally excluded), Personality disorder and reactive hypogly- underclosesupervision Itcontinuoussupervisionisnotfeasible. the cemia. A quantitative study. Diabetes withdrawal of the systemic steroid should be slower. approximately which is high in .9' 10 An in- 2 5 mg of prednisone for equivalent) every ten days. Ift withdrawal 1973; 22:664-675. symptoms appear. the previous dose of the systemic steroid should crease in alimentary fibers is also ad- 7. Yager J, Young RT: Non-hypoglycemia be resumed for a week before further decrease is attempted. is an epidemic condition. N J Med Dosage form vocated. Engl Beconase is a metered-dose aerosol, delivering 50 micrograms of If such measures are not adequate to 1974; 291:907-908. beclomethasone dipropronate with each depression of the valve with reactive 8. Hogan MJ, Service FJ, Sharbrough FW There are two hundred doses in a container permit patients hypogly- et al: Oral glucose tolerance test compared Official product monograph on request cemia to live normally, then drugs with a mixed meal in the diagnosis of reac- may be considered. However, drug tive hypoglycemia. A caveat on stimula- therapy of reactive hypoglycemia is tion. Mayo Clin Proc 1983; 58:491-496. mainly empirical, as suggested by the 9. Conn JW: The advantage of a high pro- PAAB tein diet in the treatment of spontaneous I('PP diversity of recommended agents. hypoglycemia. J Clin Invest 1936; 15:673- These include sedatives, tranquil- 678. lizers, sulfonylureas, anticholinergics, 10. Thorn GW, Quinby JT, Clinton M Jr: A Allen & Hanburys biguanides, diphenylhydantoin and comparison of the metabolic e.ffects of iso- 4 _I A Glaxo Canada Ltd. Company caloric meals of varying composition, with Toronto, Montreal propranolol.5 In my experience, a special reference to the prevention ofpost- short-acting sulfonylurea such as tol- prandial hypoglycemic symptoms. Ann In- butamide is useful in patients with tern Med 1943; 18:913-919.