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11 Ketotic hypoglycaemia
11 Ketotic Hypoglycaemia M O R E Y W. H A Y M O N D A N T H O N Y S. P A G L I A R A
In normal fasted individuals, maintenance of the plasma glucose concentration in the normal range is dependent on (1) a normal endocrine system for integrating and modulating substrate mobilization, interconversion and utilization; (2) functionally intact hepatic glycogenolytic and gluconeogenic enzymic systems; and (3) an adequate supply of endogenous metabolic fuels including potential gluconeogenic substrates (i.e. amino acids, glycerol and lactate). Adults are capable of maintaining a normal blood glucose concentration even when totally deprived of calories for weeks or, in the case of obese subjects, for months (Cahill et al, 1966). In contrast, the normal neonate and young child are unable to supply sufficient glucose to meet obligatory demands for this metabolic fuel, and exhibit a progressive fall in plasma glucose concentration to hypoglycaemic levels when fasted for even short periods of time (e.g. 24-48 hours) (Chaussain et al, 1977; Haymond et al, 1982). The reasons for this difference between the child and the adult are not entirely clear. In the postabsorptive state (4-8 hours following a meal), plasma glucose is derived primarily from hepatic glycogen, whereas with prolonged fasting the major source is gluconeogenesis. Little is known about the dynamic and quantitative aspects of glucose utilization and production in the fasted normal infant or child.
HYPOGLYCAEMIA: HISTORICAL PERSPECTIVE A group of children with recurrent hypoglycaemia was described by McQuarrie et al (1954) whose symptoms appeared usually before two years of age, exhibited a natural tendency to spontaneous remission with advancing age, and demonstrated a uniformly favourable response to treatment with a.drenocorticotrophic hormone (ACTH) or cortisone. He felt this condition represented a single clinical syndrome which he called 'idiopathic hypoglycaemia'. Two years later, Cochrane et al (1956) reported that a high protein diet increased the frequency of hypoglycaemic attacks in some of these children and suggested that leucine was the specific cause of hypoglycaemia (Table 1). With the advent of the insulin radioimmunoassay, it was demonstrated that the leucine-sensitive hypoglycaemic child exhibited an excessive insulin secretory response to this amino acid. Clinics in E n d o c r i n o l o g y a n d M e t a b o l i s m - - Vol. 12, No. 2, July 1983
0300-595X/83/12.02/447
$05.00@1983 W. B. Saunders Company Ltd
447
448
MOREY W. H A Y M O N D AND A N T H O N Y S. P A G L I A R A Table 1. Relative incidence o f childhood hypoglycaemic disorders a
Disorders Adrenal insufficiency Hypopituitarism Hypothyroidism Hepatic enzyme defects Ketotic Hyperinsulinism Undiagnosed (idiopathic) Total
MacQuarrie (1942-1954)
Kogut et al b (1964-1969)
SLCH c (1969-1972)
6 1 2 4 -1 26 40
----13 7 3 23
1 3 1 3 25 3 0 36
aTransient symptomatic hypoglycaemia of the neonate was not included. bPatients with hepatic enzyme deficiencies and hypopituitarism were not included in this study. cSt Louis Children's Hospital Experience.
Furthermore, many of the non-leucine-sensitive individuals diagnosed as having 'idiopathic hypoglycaemia' were also noted to have abnormally elevated insulin concentrations and hyperinsulinaemic responses to intravenous tolbutamide. These data suggested that idiopathic hypoglycaemia was not a single entity and that a significant number of these patients had organic hyperinsulinism. With currently available diagnostic procedures, it would appear that the majority of patients who previously would have been diagnosed as cases of idiopathic hypoglycaemia can now have the pathogenic basis of their disorder more clearly defined. This is evident from the analysis of the original patients described by McQuarrie et al (1954), the series reported by Kogut, Blaskovics and Donnell (1969), and our own experience (Table 1) (Pagliara et al, 1973). Since ketotic hypoglycaemia is the most common form of childhood hypoglycaemia, it seems reasonable that a large number of McQuarrie's original cases were examples of this disorder. His observation that a significant number of children with idiopathic hypoglycaemia exhibited spontaneous remission of their disease with increasing age and a good response to ACTH or cortisone therapy further supports our suggestion that many of these patients had ketotic hypoglycaemia. Colle and Ulstrom (1964) demonstrated that a large number of children with idiopathic hypoglycaemia developed ketosis and hypoglycaemia when fed a high fat hypocaloric diet. Criteria were established at that time for diagnosing ketotic hypoglycaemia, i.e. ketosis and hypoglycaemia within 24 hours after institution of a provocative ketogenic diet, and an absent glycaemic response to glucagon at the time of hypoglycaemia (see Figure 4). DEFINITION OF HYPOGLYCAEMIA The definition of hypoglycaemia must be considered in the context of the clinical (duration of fasting and age) and biochemical findings (presence of increased FFA and ketone body concentrations) at that time. Children usually develop symptoms of hypoglycaemia at plasma glucose concentrations of less than 40 mg/dl. Any child or infant who develops a plasma
449
KETOTIC HYPOGLYCAEMIA
glucose ~ 50 mg/dl must be carefully observed; and at concentrations of 40 mg/dl, the child should be considered to be hypoglycaemic, and diagnostic and therapeutic intervention initiated. The clinical findings associated with a rapid fall in the plasma glucose concentration are primarily adrenergic in character (i.e. sweating, weakness, tachycardia and nervousness), most likely reflecting increased epinephrine secretion. If the hypoglycaemia is not relieved, manifestations of cerebral dysfunction such as headache, irritability, mental confusion, psychotic behaviour, seizures and coma become progressively more prominent. With frequent or prolonged episodes of hypoglycaemia, permanent central nervous system dysfunction may result. It should be emphasized that these signs and symptoms of hypoglycaemia in the young infant are either less obvious or absent. M E T A B O L I C R E S P O N S E TO F A S T I N G IN C H I L D R E N AND ADULTS
In a recent study (Haymond et al, 1982), the metabolic differences and responses to a short-term fasting were examined in men, women and children. Glucose concentrations were similar in the three groups studied during the first 18 hours of fasting (Figure 1). By 30 hours, the plasma
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Figure 1. P l a s m a glucose concentrations from ten m e n and ten women during 84 hours o f fasting and 15 prepubertal children during a 30 hour fast. Zero time o f the fast was 1800 hours, 1 hour following their last meal. All data are expressed as the m e a n _+ s.e. F r o m H a y m o n d et al (1982), with kind permission o f the authors and the editor of Metabolism.
450
M O R E Y W. H A Y M O N D A N D A N T H O N Y S. P A G L I A R A
glucose concentration was lowest in children and highest in men (children 53 _ 3 mg/dl, women 64 _+ 3 m g / d l and men 72 _ 3 mg/dl). The glucose concentrations were higher in men than in women (P < 0.001), and higher in the adults than in the children (P < 0.05) throughout the entire period o f study. Postprandial /3-hydroxybutyrate and acetoacetate concentrations were similar and rose progressively during fasting in all three groups (Figure 2). Ketone body concentrations rose m o r e rapidly and to higher values in children than in adults over the initial 30 hours of fasting. The level of ketonaemia observed in the children was not reached in the women until 56
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Figure 2. Blood /3-hydroxybutyrate and acetoacetate concentrations from ten m e n and ten w o m e n during 84 hours o f fasting and 15 prepubertal children during a 30 hour fast. Zero time of the fast was 1800 hours, 1 hour following their last meal. All data are expressed as the m e a n - s.e. From H a y m o n d et al (1982), with kind permission o f the authors and editor o f
Metabolism.
451
KETOTIC H Y P O G L Y C A E M I A
hours of fasting, and was never achieved in the men. During the entire period of study, /3-hydroxybutyrate concentrations were higher in women than in men, while no significant differences in acetoacetate concentrations were observed. An inverse relationship was observed between plasma glucose and /3-hydroxybutyrate concentrations in each group ( H a y m o n d et al, 1982). Postprandial alanine concentrations (Figure 3) were similar in men, women and children and decreased over the initial 30 hours of fasting. The decrease in alanine concentrations was greatest in the children (280 ~M at 30 hours) as compared with men (120/~M) or women (180/~M). Plasma insulin concentrations were similar in men, women and children immediately following their last meal. These concentrations progressively decreased over the first 24 hours of fasting in all subjects and subsequently remained between 3 and 6 g u / m l . Plasma insulin concentrations may have been lower in the children when compared with those of the adults over the l a s t 8 hours of study (i.e. between 22 and 30 hours o f fasting) since a number of values were below the sensitivity of the insulin assay (less than 2 g u / m l ) ( H a y m o n d et al, 1982). No significant differences were observed in glucagon or cortisol concentrations during the entire fast. Epinephrine and norepinephrine concentrations were measured in adults during a similar fasting study but only minimal changes were observed (Cryer, unpublished data). To date, these latter two hormones have not been examined in children during short-term
400
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TIME Figure 3. Plasma alanine concentrations from ten men and ten women during 84 hours of fasting and 15 prepubertal children during a 30 hour fast. Zero time of the fast was 1800 hours, 1 hour following their last meal. All data are expressed as the mean _+ s.e. From H a y m o n d et al (1982), with kind permission of the authors and the editor of Metabolism.
452
M O R E Y W. H A Y M O N D A N D A N T H O N Y S. P A G L I A R A
fasting. From the above studies it is concluded that the differences in glucose, ketone bodies and alanine concentrations in men, women and children cannot be explained on changes in hormonal secretion. On a per kg body weight basis, rates of glucose flux (production and utilization) in adults are approximately 2.2 mg/kg/min in the postabsorptive state (14 hours of fasting) and decrease to about 1.2 mg/kg/min by 30 hours of fasting. The rate of glucose flux in infants and children following 4-14 hours of fasting is nearly three times higher (5-7 mg/kg/min) than that of adults and decreases to 3 -4 mg/kg/min following a 30-40 hour fast (Bier et al, 1977; Haymond et al, 1978). Since the brain is the primary glucose utilizing tissue of the body, it is not surprising that the rate of glucose flux is linearly related to estimated brain weight and not to body weight (Bier et al, 1977). This observation is in keeping with earlier speculation that the relative increase in brain mass to body size places infants and children at particular risk for hypoglycaemia (Cornblath and Schwartz, 1976). It becomes evident from the above considerations that the young child is in a precarious balance between their obligatory glucose requirements and his ability to maintain an adequate supply of glucose during caloric deprivation. Despite the observed increase in glucose requirements, the hepatic glycogen content in normal children is sufficient to meet these demands for at least 14 to 18 hours. After 24 to 36 hours of fasting, the young child is totally dependent on gluconeogenesis; this is reflected clinically by the blunted or absent glycaemic response to exogenous glucagon under these fasting conditions (Pagliara et al, 1972). As much as 50 per cent of hepatic glucose production following prolonged fasting in adults is derived from amino acids of which muscle is a major source (Cahill, 1970). Since the muscle mass of newborns, infants and young children relative to body mass is smaller than that of adults (Cornblath and Schwartz, 1976), the ability to mobilize sufficient endogenous gluconeogenic substrate to maintain the higher rates of glucose production may be compromised in these immature individuals. Although the metabolic response to fasting in children is similar to that of adults, the lower plasma glucose and higher plasma ketone body concentrations during brief periods of fasting in children suggest that the relative increase in glucose requirement in children may result in an acceleration of the normal adaptive mechanisms observed in adults (Haymond et al, 1982). As a result, abnormalities in the modulation of substrate mobilization, interconversion and utilization in children are frequently accompanied by hypoglycaemia. KETOTIC HYPOGLYCAEMIA Ketotic hypoglycaemia has been the most common form of childhood hypoglycaemia reported (Kogut, Blaskovics and Donnell, 1969; Pagliara et al, 1973). This disorder classically manifests itself between 18 months and 5 years of age and generally remits spontaneously before 8 to 9 years. Early studies focused on hepatic gluconeogenic enzyme deficiencies and/or
KETOTIC HYPOGLYCAEMIA
453
functional disturbances of insulin secretion to elucidate the pathophysiology of the hypoglycaemia in this syndrome. These studies have demonstrated that: glucagon evokes a normal glycaemic response in these children in the fed state (Figure 4) (Colle and Ulstrom, 1964; Pagliara et al, 1972), indicating the presence of hepatic glycogen and normal activity of glycogenolytic enzymes (phosphorylase, amylo-l,6-glucosidase, and glucose-6phosphatase) (Figure 5); infusions of fructose (Colle and Ulstrom, 1964) and glycerol (Senior and Loridan, 1969) result in a prompt increase in plasma blood glucose concentration, thus indicating normal activities of fructose-l,6-diphosphatase and glucose-6-phosphatase; plasma glycerol levels in the fed and fasted states are no different from those of similarly treated control children (Haymond, Karl and Pagliara, 1974), indicating that this substrate is not rate-limiting; responses to infusions of/3-hydroxybutyrate do not differ from those of normal children (Loridan and Senior, 1970); plasma insulin concentrations are appropriately low (Senior and Loridan, 1969; Grunt et al, 1970; Pagliara et al, 1972) and those of glucagon and cortisol are increased at the time of hypoglycaemia (Haymond, Karl and Pagliara, 1974). BEFORE DIET
AFTER 0 •
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Figure 4. Response to intravenous injection of 0.03 mg/kg glucagon before and after the provocative ketogenic diet. From Pagliara et al (1972), with kind permission of the authors and the editor of Journal of Clinical Investigation.
454
MOREY W. HAYMOND AND ANTHONY S. PAGLIARA
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\ ......./.. Figure 5. Metabolic pathways involved in glycogen synthesis and degradation and gluco-
neogenesis. Key enzymesare designated by number (1) glucose-6-phosphate,(2) glucokinase, (3) amylo-l,6-glucosidase, (4) phosphorylase, (5) phosphoglucomutase, (6) glycogen synthetase, (7) galactokinase, (8) galactose-1,-phosphate uridyl transferase, (9) uridine diphosphogalactose-4-epimerase,(10) phosphofructokinase, (11) fructose-l,6-diphosphatase, (12) fructose-l,6-diphosphatealdolase, (13) fructokinase, (14) fructose-l-phosphate aldolase; (15) phosphoenolpyruvatecarbodylase, (16) pyruvate carboxylase.From Pagliara et al (1973), with kind permission of the authors and the editor of Journal of Pediatrics. In these children, symptomatic hypoglycaemia and ketonaemia develop 8 to 16 hours following the initiation o f a hypocaloric ketogenic diet (1200 kcal per 1.73 m 2 body surface, 63 per cent fat, 17 per cent protein, 15 per cent carbohydrate) (Colle and Ulstrom, 1964). Normal children exhibit similar biochemical findings after 32 to 36 hours on the same dietary regimen, but do not develop symptomatic hypoglycaemia (Pagliara et al, 1972) (Figure 6). Comparable results have been obtained with fasting alone, thus indicating that the hypoglycaemia occurring during the ketogenic diet challenge is a consequence of its hypocaloric nature, rather than its fat content (Haymond, Karl and Pagliara, 1974) (Figure 7). Following an overnight fast, plasma glucose concentrations in children with ketotic hypoglycaemia are similar to age-matched normals. A provocative 24-hour fast (beginning after the evening meal) provides the advantage of inducing hypoglycaemia during the child's waking hour (16- 24 hours of fasting). Children with ketotic hypoglycaemia have normal venous lactate and pyruvate concentrations, but have hypoalaninaemia prior to and during either fasting or ketogenic diet challenge (Pagliara et al, 1972; Haymond,
KETOTIC HYPOGLYCAEMIA
455
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Figure 6. Substrate changes after the ketogenic diet in ketotic hypoglycaemiaand control children. From Pagliara et al (1972), with kind permission of the authors and the editor of Journal of Clinical Investigation.
Karl and Pagliara, 1974) (Figures 6 and 7). The low plasma insulin and high FFA and ketone body concentrations virtually exclude hyperinsulinaemia as an aetiological factor (Colic and Ulstrom, 1964; Grunt et al, 1970; Loridan and Senior, 1970; Haymond, Karl and Pagliara, 1974). Glucocorticoid insufficiency can be excluded since plasma cortisol concentrations are higher in children with ketotic hypoglycaemia than those of normal children even prior to the development of fasting hypoglycaemia (Figure 8). In addition, tests of the pituitary adrenal axis are normal (Colle and Ulstrom, 1964; Senior and Loridan, 1969). No differences were observed in plasma growth hormone or glucagon in the ketotic hypoglycaemic children when compared with those of normal children until hypoglycaemia had ensued, at which time they appropriately increased (Figure 9). Infusion of alanine (250 mg/kg body weight) in these children produces a rise in plasma glucose ( A 15-25 mg/dl by min 15-30) without prominent changes in blood lactate, pyruvate or insulin concentrations (Pagliara et al, 1972; Haymond, Karl and Pagliara, 1974) (Figure 10). This response indicates that the entire gluconeogenic pathway from the level of pyruvate is intact, and hence a gluconeogenic enzyme defect can be excluded (Figure 5). Treatment with large doses of glucocorticoids prior to or during the administration of the ketogenic diet prevents the development of hypoglycaemia and ketosis (Colle and Ulstrom, 1964; Pagliara et al, 1972) (Figure 11). Within 4 to 6 hours of glucocorticoid administration, plasma alanine and glutamine concentrations increase two- to threefold (Pagliara
456
MOREY W. HAYMOND AND ANTHONY S. PAGLIARA
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Figure 7. Glucose, fl-hydroxybutyrate + acetoacetate, glycerol, and insulin responses to fasting in normal and ketotic hypoglycaemic (KH) children. Values represent the mean _+SEM. From Haymond, Karl and Pagliara (1974), with kind permission of the editor of Journal o f Clinical Endocrinology and Metabolism.
et al, 1972). These results suggest that the protection from hypoglycaemia afforded by glucocorticoid therapy is a result of its acute catabolic effect on muscle protein, rather than induction of increased levels of hepatic gluconeogenic enzymes. POSSIBLE PATHOPHYSIOLOGICAL FACTORS CAUSING KETOTIC HYPOGLYCAEMIA The mechanisms responsible for the hypoalaninaemia and hypoglycaemia in these patients remains unknown. Since the major source of endogenous gluconeogenic amino acids is skeletal muscle, a defect in any of the enzymes or hormone-sensitive sites involved in protein catabolism, transamination, or amino acid efflux in this tissue might represent a potential aetiological basis for this disorder. On the other hand, in the original clinical description of this syndrome, it was pointed out that these children frequently are smaller than age-matched control subjects (Colle and Ulstrom, 1964; Grunt et al, 1970; Pagliara et al, 1972). Because of the increased glucose requirement on a per kg body weight basis in the young child, when compared with adults, any modest compromise in the supply of endogenous gluconeogenic substrates (e.g. amino acid from decreased muscle mass, independent of a specific enzyme or hormone defect) might predispose to the development of hypoglycaemia and ketosis. In this context, ketotic hypoglycaemia may
457
KETOTIC HYPOGLYCAEMIA
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Figure 8. Glucose, alanine, lactate and pyruvate responses to fasting in normal and ketotic hypoglycaemic (KH) children. Values represent the mean _+SEM. From Haymond, Karl and Pagliara (1974), with kind permission of the editor of Journal o f Clinical Endocrinology and Metabolism.
constitute one end o f a spectrum representing the normal distribution pattern of tolerance to fasting (Senior, 1973). In all previous studies with ketotic hypoglycaemic children, plasma concentrations have been the index of gluconeogenic availability. Without measurements of the rates o f alanine appearance and disappearance, as well as conversion rates of potential gluconeogenic substrates to glucose during the evolution of hypoglycaemia, the hypothesis that the hypoglycaemia is substrate limitation remains to be proved. Following an overnight fast and at a time when the plasma concentrations of glucose are normal, the rates of glucose flux were similar between normal children and those with ketotic hypoglycaemia. In contrast, rates of alanine production in ketotic hypoglycaemic children were lower than normals (Table 2), which is consistent with the postulate of substrate limitation. The contribution o f alanine to hepatic glucose production in the adult in the postabsorptive state is approximately 2 to 4 per cent (Clarke et al, 1979), but may be significantly higher with prolonged fasting (Cahill, 1970). The contribution of alanine and other 'potential' gluconeogenic amino acids to hepatic glucose production in children is unknown. In children and particularly the child with ketotic hypoglycaemia, plasma substrate and hormonal concentrations during short-term fasts are consistent with a more accelerated state o f fasting, as compared to c o m p a r a b l y fasted adults (Figures 1, 2 and 7). When the total plasma concentration o f 18-acid neutral
458
MOREY W. H A Y M O N D AND A N T H O N Y S. P A G L I A R A
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Figure 9. Glucose, cortisol, growth hormone, glucagon, insulin and insulin/glucagon ratio (I/G) responses to fasting in normal and ketotic hypoglycaemic children. Values represent the mean _+ SEM. From Haymond, Karl and Pagliara (1974), with kind permission of the editor of Journal o f Clinical Endocrinology and Metabolism.
amino acids was measured, there was a significant decrease in the plasma concentration of 'potential' total gluconeogenic amino acids in the ketotic hypoglycaemic children throughout the fast, which was lower than those of similarly fasted children (Haymond, Karl and Pagliara, 1974). If one could project from the alanine turnover studies cited above (Table 2), substrate limitation in the form of gluconeogenic amino acid deficiency could result in a small decrease in glucose production which, if persistent throughout the fast, could account for the hypoglycaemia seen in this disorder. Confirmation of this hypothesis awaits further turnover studies in these children. The rapid development of ketosis in children, when compared with adults (Figure 2), is temporarily associated with the fall in both plasma concentrations of glucose and insulin. This propensity to develop ketosis is further accentuated in the child with ketotic hypoglycaemia (Figure 7). Since ketone
459
KETOTIC HYPOGLYCAEMIA i.v. Alonlne 250 mg/kg
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Figure 11. Response to the provocative ketogenic diet with and without cortisone acetate administration. Patient D.C. underwent two challenges with the ketogenic diet. Oral cortisone acetate 40 mg every six hours for three doses was administered during the second challenge. The response to intravenous glucagon 0.03 mg/kg body weight is shown at the bottom of the figure, 18 hours after the first, and 24 hours after the second challenge. From Pagliara et al (1972), with kind permission of the editor of Journal of Clinical Investigation.
460
MOREY W. H A Y M O N D AND A N T H O N Y S. P A G L I A R A
Table 2. Rates o f glucose and alanine f l u x in normal children and patients with ketotic
hypoglycaemia after an overnight fast
Normal children ( N = 8 ) Ketotic hypoglycaemic children (N = 10)
Glucose fluxa /~mol/kg/min
Alanine flux b /~mol/kg/min
32 _+ 9 34 +_ 3
15 _+ 2 9 _+ 1
aDetermined utilizing a constant in fusion of D [6,6-2 H 2] glucose. bDetermined utilizing a constant infusion of L-[2,3,3,3-2H4] alanine and venous blood sampling.
bodies are insulin secretogogues in man (Miles, Haymond and Gerich, 1980), it is possible that the hyperketonaemia in normal and ketotic hypoglycaemic children could stimulate small increases in portal insulin concentrations, which could result in decreased hepatic glucose production without affecting peripheral plasma insulin concentrations. The accelerated ketosis seen in children as compared with adults is most likely due to increased rates of production. The hyperketonaemia may be important in the maintenance of glucose homeostasis during fasting since ketones can be utilized by brain, thus decreasing obligate glucose requirements (Owen et al, 1967). In the children with ketotic hypoglycaemia, the higher plasma ketone body concentrations could be a result of heightened ketone body production as compared to normal, or alternatively a decrease in ketone body utilization. If such a decrease in utilization were at the level of the central nervous system, glucose would be primarily utilized resulting in an accelerated rate of glucsoe utilization during the evolution of hypoglycaemia which outstrips the child's total capacity to produce glucose. This could account for the accelerated changes in the circulating concentrations of metabolic fuels and hormones observed with fasting or with ketogenic diet provocation in this disorder. Until measurements of rates of production and utilization of glucose, alanine, ketone bodies and of plasma C-peptide concentrations have been performed during the evolution of the hypoglycaemia in this disorder, it cannot be determined which, if any, of the possibilities discussed above are involved in the pathophysiology of this disorder. Some studies have implicated abnormal adrenal medullary response in children with ketotic hypoglycaemia. Decreased urinary catecholamine excretion has been documented in these children in response to insulin, 2-deoxyglucose and the ketogenic diet (Broberger and Zetterstrom, 1961; Koffler, Shubert and Hug, 1971), as well as abnormally low plasma epinephrine concentration during insulin-induced hypoglycaemia (Christensen, 1974). The pathophysiological role that epinephrine insufficiency may play in the hypoglycaemia and hypoalaninaemia in this disorder remain to be elucidated since adrenalectomized adults recover normally from insulin-induced hypoglycaemia, provided glucagon secretion is intact (Cryer, 1981). Whatever the cause, it would seem reasonable to propose that the underlying deficit is present from birth, but is not manifested until the child
KETOTIC HYPOGLYCAEMIA
461
encounters a catabolic stress such as infection or periods of caloric restriction. Furthermore, as the supply of endogenous substrate increases relative to glucose d e m a n d (i.e. with age), one might expect spontaneous remission to occur. M A N A G E M E N T OF C H I L D R E N W I T H K E T O T I C HYPOGLYCAEMIA Ketotic hypoglycaemia is a self-limited disorder that predictably remits by 8- 9 years o f age. The hypoglycaemia usually occurs in association with intercurrent infections, or during periods in which caloric restriction is sustained for 12 hours or more. Treatment consists of frequent feeding (4 - 5 meals per day) o f a high protein, high carbohydrate diet (Colle and Ulstrom, 1964). Parents should be instructed to test the child's urine for ketones during periods o f illness, since ketonuria usually precedes hypoglycaemia by several hours. Under these circumstances, oral or parenteral glucose should be administered to prevent the development of hypoglycaemia. SUMMARY
Ketotic hypoglycaemia is the most c o m m o n f o r m of childhood hypoglycaemia. This disorder classically manifests itself between the ages of 18 months and 5 years, and generally remits spontaneously before 8 or 9 years of age. A presumptive diagnosis is made by documenting a low blood sugar in association with ketonuria, ketonaemia and typical s y m p t o m s of hypoglycaemia. The definitive diagnosis is established by demonstrating an inability to tolerate a provocative ketogenic diet, or a fast. Susceptible or affected children develop severe hypoglycaemia and ketosis on this diet within 24 hours. Plasma alanine concentrations on either a normal or ketogenic diet were significantly lower in ketotic hypoglycaemic children c o m p a r e d with normal children. In contrast to adults, even normal children develop hypoglycaemia and ketonaemia when calorically deprived for relatively short periods o f time (32 to 36 hrs). ACKNOWLEDGEMENTS
The authors were supported in part by the Mayo and Wasie foundations and USPHS AM-26989, and Gunderson Medical Foundation Ltd, with funds from the Trane Foundation, respectively.
REFERENCES
Bier, D. M., Leake, R. D., Arnold, K. J. et al (1977) Measurement of 'true' glucose production rates with 6,6-dideuterioglucose. Diabetes, 26, 1016-1023. Broberger, O. & Zetterstrom, R. (1961) Hypoglycemia with an inability to increase the epinephrine secretion in insulin-induced hypoglycemia.Journal of Pediatrics, 59, 215-222. Cahill, G. H., Jr (1970) Starvation in man. New England Journal of Medicine, 282, 668.
462
MOREY W. HAYMOND AND ANTHONY S. PAGLIARA
Cahill, G. F., Jr, Herrera, M. G., Morgan, A. P. et al (1966) Hormone fuel interrelationships during fasting. Journal of Clinical Investigation, 45, 1751. Chaussain, J. L., Georges, P., Olive, G. et al (1974) Glycemic response to 24-hour fast in normal children and children with ketotic hypoglycemia II: Hormonal and metabolic changes. Journal of Pediatrics, 85, 776-781. Chaussain, J. L., Georges, P., Calzada, L. et al (1977) Glycemic response to 24-hour fast in normal children. III. Influence of age. Journal of Pediatrics, 91, 711-714. Christeusen, N. J. (1974) Hypoadrenalinemia during insulin hypoglycemia in children with ketotic hypoglycemia. Journal of Clinical Endocrinology and Metabolism, 38, 107-112. Clarke, W. L., Santiago, J. V., Thomas, L. et al (1979) Adrenergic mechanisms in recovery from hypoglycemia in man: Adrenergic blockage. American Journal of Physiology, 236, E149-E152. Cochrane, W. A., Payne, W. W., Simpkiss, M. J. & Woolf, L. I. (1956) Familial hypoglycemia precipitated by amino acids. Journal of Clinical Investigation, 35, 411-422. Colle, E. & Ulstrom, R. A. (1964) Ketotic hypoglycemia. Journal of Pediatrics, 64, 632-651. Cornblath, M. & Schwartz, R. (1976) Disorders of Carbohydrate Metabolism in Infancy. 2rid edition, Philadelphia: W. B. Saunders. Cryer, P. E. (1981) Glucose counterregulation in man. Diabetes, 30, 261-264. Grunt, J. A., McGarry, M. E., McCollum, A. T. & Gould, J. B. (1970) Studies of children with ketotic hypoglycemia. Yale Journal of Biological Medicine, 42, 420-438. Haymond, M. W., Karl, I. E., Pagliara, A. S. (1974) Ketotic hypoglycemia: An amino acid substrate limited disorder. Journal of Clinical Endocrinology and Metabolism, 38, 521-530. Haymond, M. W., Strobel, K., Galim, B. & DeVivo, D. (1978) Effects of ketosis on glucose and alanine fluxes in children. Clinical Research, 25, 682A. Haymond, M. W., Karl, E., Clarke, W. L. et al (1982) Differences in circulating gluconeogenic substrates during short-term fasting in men, women and children. Metabolism, 31, 33-42. Koffler, H., Schubert, W. K. & Hug, G. (1971) Sporadic hypoglycemia: Abnormal epinephrine response to the ketogenic diet or to insulin. Journal of Pediatrics, 78, 448-453. Kogut, M. D., Blaskovics, M. & Donnell, G. N. (1969) Idiopathic hypoglycemia: A study of twenty-six children. Journal of Pediatrics, 74, 853-871. Loridan, L. & Senior, B. (1970) Effects of infusion of ketones in children with ketotic hypoglycemia. Journal of Pediatrics, 76, 69-74. McQuarrie, I., Bell, E. T., Zimmerman, B. & Wright, W. S. (1954) Deficiency of alpha cells of pancreas as possible etiological factor in familial hypoglycemia. Federation Proceedings, 9, 337. Miles, J. M., Haymond, M. W. & Gerich, J. E. (1980) Suppression of glucose production and stimulation of insulin secretion by physiological concentrations of ketone bodies in man. Journal of Clinical Endocrinology and Metabolism, 52, 34-37. Owen, O. E., Morgan, A. P., Kemp, H. G. et al (1967) Brain metabolism during fasting. Journal of Clinical Investigation, 46, 1589-1597. Pagliara, A. S., Karl, I. E., DeVivo, D. C. et al (1972) Hypoalaninemia: A concomitant of ketotic hypoglycemia. Journal of Clinical Investigation, 51, 1440-1449. Pagliara, A. S., Karl I. E., Haymond, M. W. & Kipnis, D. M. (1973) Hypoglycemia in infancy and childhood. Parts I and II. Journal of Pediatrics, 82, 365-379, 558-577. Senior, B. (1973) Ketotic hypoglycemia. Journal of Pediatrics, 82, 555-556. Senior, B. & Loridan, L. (1969) Gluconeogenesis and insulin in the ketotic variety of childhood hypoglycemia and in control children. Journal of Pediatrics, 74, 529-539. Sizonenko, P. C., Paunier, L., Vallotton, J. B. et al (1973) Response to 2-Deoxy-D-glucose and to glucagon in ketotic hypoglycemia of childhood. Evidence for epinephrine deficiency and altered alanine availability. Pediatric Research, 7, 983-993.
In normal fasted individuals, maintenance of the plasma glucose concentration in the normal range is dependent on (1) a normal endocrine system for integrating and modulating substrate mobilization, interconversion and utilization; (2) functionally intact hepatic glycogenolytic and gluconeogenic enzymic systems; and (3) an adequate supply of endogenous metabolic fuels including potential gluconeogenic substrates (i.e. amino acids, glycerol and lactate). Adults are capable of maintaining a normal blood glucose concentration even when totally deprived of calories for weeks or, in the case of obese subjects, for months (Cahill et al, 1966). In contrast, the normal neonate and young child are unable to supply sufficient glucose to meet obligatory demands for this metabolic fuel, and exhibit a progressive fall in plasma glucose concentration to hypoglycaemic levels when fasted for even short periods of time (e.g. 24-48 hours) (Chaussain et al, 1977; Haymond et al, 1982). The reasons for this difference between the child and the adult are not entirely clear. In the postabsorptive state (4-8 hours following a meal), plasma glucose is derived primarily from hepatic glycogen, whereas with prolonged fasting the major source is gluconeogenesis. Little is known about the dynamic and quantitative aspects of glucose utilization and production in the fasted normal infant or child.
HYPOGLYCAEMIA: HISTORICAL PERSPECTIVE A group of children with recurrent hypoglycaemia was described by McQuarrie et al (1954) whose symptoms appeared usually before two years of age, exhibited a natural tendency to spontaneous remission with advancing age, and demonstrated a uniformly favourable response to treatment with a.drenocorticotrophic hormone (ACTH) or cortisone. He felt this condition represented a single clinical syndrome which he called 'idiopathic hypoglycaemia'. Two years later, Cochrane et al (1956) reported that a high protein diet increased the frequency of hypoglycaemic attacks in some of these children and suggested that leucine was the specific cause of hypoglycaemia (Table 1). With the advent of the insulin radioimmunoassay, it was demonstrated that the leucine-sensitive hypoglycaemic child exhibited an excessive insulin secretory response to this amino acid. Clinics in E n d o c r i n o l o g y a n d M e t a b o l i s m - - Vol. 12, No. 2, July 1983
0300-595X/83/12.02/447
$05.00@1983 W. B. Saunders Company Ltd
447
448
MOREY W. H A Y M O N D AND A N T H O N Y S. P A G L I A R A Table 1. Relative incidence o f childhood hypoglycaemic disorders a
Disorders Adrenal insufficiency Hypopituitarism Hypothyroidism Hepatic enzyme defects Ketotic Hyperinsulinism Undiagnosed (idiopathic) Total
MacQuarrie (1942-1954)
Kogut et al b (1964-1969)
SLCH c (1969-1972)
6 1 2 4 -1 26 40
----13 7 3 23
1 3 1 3 25 3 0 36
aTransient symptomatic hypoglycaemia of the neonate was not included. bPatients with hepatic enzyme deficiencies and hypopituitarism were not included in this study. cSt Louis Children's Hospital Experience.
Furthermore, many of the non-leucine-sensitive individuals diagnosed as having 'idiopathic hypoglycaemia' were also noted to have abnormally elevated insulin concentrations and hyperinsulinaemic responses to intravenous tolbutamide. These data suggested that idiopathic hypoglycaemia was not a single entity and that a significant number of these patients had organic hyperinsulinism. With currently available diagnostic procedures, it would appear that the majority of patients who previously would have been diagnosed as cases of idiopathic hypoglycaemia can now have the pathogenic basis of their disorder more clearly defined. This is evident from the analysis of the original patients described by McQuarrie et al (1954), the series reported by Kogut, Blaskovics and Donnell (1969), and our own experience (Table 1) (Pagliara et al, 1973). Since ketotic hypoglycaemia is the most common form of childhood hypoglycaemia, it seems reasonable that a large number of McQuarrie's original cases were examples of this disorder. His observation that a significant number of children with idiopathic hypoglycaemia exhibited spontaneous remission of their disease with increasing age and a good response to ACTH or cortisone therapy further supports our suggestion that many of these patients had ketotic hypoglycaemia. Colle and Ulstrom (1964) demonstrated that a large number of children with idiopathic hypoglycaemia developed ketosis and hypoglycaemia when fed a high fat hypocaloric diet. Criteria were established at that time for diagnosing ketotic hypoglycaemia, i.e. ketosis and hypoglycaemia within 24 hours after institution of a provocative ketogenic diet, and an absent glycaemic response to glucagon at the time of hypoglycaemia (see Figure 4). DEFINITION OF HYPOGLYCAEMIA The definition of hypoglycaemia must be considered in the context of the clinical (duration of fasting and age) and biochemical findings (presence of increased FFA and ketone body concentrations) at that time. Children usually develop symptoms of hypoglycaemia at plasma glucose concentrations of less than 40 mg/dl. Any child or infant who develops a plasma
449
KETOTIC HYPOGLYCAEMIA
glucose ~ 50 mg/dl must be carefully observed; and at concentrations of 40 mg/dl, the child should be considered to be hypoglycaemic, and diagnostic and therapeutic intervention initiated. The clinical findings associated with a rapid fall in the plasma glucose concentration are primarily adrenergic in character (i.e. sweating, weakness, tachycardia and nervousness), most likely reflecting increased epinephrine secretion. If the hypoglycaemia is not relieved, manifestations of cerebral dysfunction such as headache, irritability, mental confusion, psychotic behaviour, seizures and coma become progressively more prominent. With frequent or prolonged episodes of hypoglycaemia, permanent central nervous system dysfunction may result. It should be emphasized that these signs and symptoms of hypoglycaemia in the young infant are either less obvious or absent. M E T A B O L I C R E S P O N S E TO F A S T I N G IN C H I L D R E N AND ADULTS
In a recent study (Haymond et al, 1982), the metabolic differences and responses to a short-term fasting were examined in men, women and children. Glucose concentrations were similar in the three groups studied during the first 18 hours of fasting (Figure 1). By 30 hours, the plasma
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Figure 1. P l a s m a glucose concentrations from ten m e n and ten women during 84 hours o f fasting and 15 prepubertal children during a 30 hour fast. Zero time o f the fast was 1800 hours, 1 hour following their last meal. All data are expressed as the m e a n _+ s.e. F r o m H a y m o n d et al (1982), with kind permission o f the authors and the editor of Metabolism.
450
M O R E Y W. H A Y M O N D A N D A N T H O N Y S. P A G L I A R A
glucose concentration was lowest in children and highest in men (children 53 _ 3 mg/dl, women 64 _+ 3 m g / d l and men 72 _ 3 mg/dl). The glucose concentrations were higher in men than in women (P < 0.001), and higher in the adults than in the children (P < 0.05) throughout the entire period o f study. Postprandial /3-hydroxybutyrate and acetoacetate concentrations were similar and rose progressively during fasting in all three groups (Figure 2). Ketone body concentrations rose m o r e rapidly and to higher values in children than in adults over the initial 30 hours of fasting. The level of ketonaemia observed in the children was not reached in the women until 56
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Metabolism.
451
KETOTIC H Y P O G L Y C A E M I A
hours of fasting, and was never achieved in the men. During the entire period of study, /3-hydroxybutyrate concentrations were higher in women than in men, while no significant differences in acetoacetate concentrations were observed. An inverse relationship was observed between plasma glucose and /3-hydroxybutyrate concentrations in each group ( H a y m o n d et al, 1982). Postprandial alanine concentrations (Figure 3) were similar in men, women and children and decreased over the initial 30 hours of fasting. The decrease in alanine concentrations was greatest in the children (280 ~M at 30 hours) as compared with men (120/~M) or women (180/~M). Plasma insulin concentrations were similar in men, women and children immediately following their last meal. These concentrations progressively decreased over the first 24 hours of fasting in all subjects and subsequently remained between 3 and 6 g u / m l . Plasma insulin concentrations may have been lower in the children when compared with those of the adults over the l a s t 8 hours of study (i.e. between 22 and 30 hours o f fasting) since a number of values were below the sensitivity of the insulin assay (less than 2 g u / m l ) ( H a y m o n d et al, 1982). No significant differences were observed in glucagon or cortisol concentrations during the entire fast. Epinephrine and norepinephrine concentrations were measured in adults during a similar fasting study but only minimal changes were observed (Cryer, unpublished data). To date, these latter two hormones have not been examined in children during short-term
400
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6P.M.
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TIME Figure 3. Plasma alanine concentrations from ten men and ten women during 84 hours of fasting and 15 prepubertal children during a 30 hour fast. Zero time of the fast was 1800 hours, 1 hour following their last meal. All data are expressed as the mean _+ s.e. From H a y m o n d et al (1982), with kind permission of the authors and the editor of Metabolism.
452
M O R E Y W. H A Y M O N D A N D A N T H O N Y S. P A G L I A R A
fasting. From the above studies it is concluded that the differences in glucose, ketone bodies and alanine concentrations in men, women and children cannot be explained on changes in hormonal secretion. On a per kg body weight basis, rates of glucose flux (production and utilization) in adults are approximately 2.2 mg/kg/min in the postabsorptive state (14 hours of fasting) and decrease to about 1.2 mg/kg/min by 30 hours of fasting. The rate of glucose flux in infants and children following 4-14 hours of fasting is nearly three times higher (5-7 mg/kg/min) than that of adults and decreases to 3 -4 mg/kg/min following a 30-40 hour fast (Bier et al, 1977; Haymond et al, 1978). Since the brain is the primary glucose utilizing tissue of the body, it is not surprising that the rate of glucose flux is linearly related to estimated brain weight and not to body weight (Bier et al, 1977). This observation is in keeping with earlier speculation that the relative increase in brain mass to body size places infants and children at particular risk for hypoglycaemia (Cornblath and Schwartz, 1976). It becomes evident from the above considerations that the young child is in a precarious balance between their obligatory glucose requirements and his ability to maintain an adequate supply of glucose during caloric deprivation. Despite the observed increase in glucose requirements, the hepatic glycogen content in normal children is sufficient to meet these demands for at least 14 to 18 hours. After 24 to 36 hours of fasting, the young child is totally dependent on gluconeogenesis; this is reflected clinically by the blunted or absent glycaemic response to exogenous glucagon under these fasting conditions (Pagliara et al, 1972). As much as 50 per cent of hepatic glucose production following prolonged fasting in adults is derived from amino acids of which muscle is a major source (Cahill, 1970). Since the muscle mass of newborns, infants and young children relative to body mass is smaller than that of adults (Cornblath and Schwartz, 1976), the ability to mobilize sufficient endogenous gluconeogenic substrate to maintain the higher rates of glucose production may be compromised in these immature individuals. Although the metabolic response to fasting in children is similar to that of adults, the lower plasma glucose and higher plasma ketone body concentrations during brief periods of fasting in children suggest that the relative increase in glucose requirement in children may result in an acceleration of the normal adaptive mechanisms observed in adults (Haymond et al, 1982). As a result, abnormalities in the modulation of substrate mobilization, interconversion and utilization in children are frequently accompanied by hypoglycaemia. KETOTIC HYPOGLYCAEMIA Ketotic hypoglycaemia has been the most common form of childhood hypoglycaemia reported (Kogut, Blaskovics and Donnell, 1969; Pagliara et al, 1973). This disorder classically manifests itself between 18 months and 5 years of age and generally remits spontaneously before 8 to 9 years. Early studies focused on hepatic gluconeogenic enzyme deficiencies and/or
KETOTIC HYPOGLYCAEMIA
453
functional disturbances of insulin secretion to elucidate the pathophysiology of the hypoglycaemia in this syndrome. These studies have demonstrated that: glucagon evokes a normal glycaemic response in these children in the fed state (Figure 4) (Colle and Ulstrom, 1964; Pagliara et al, 1972), indicating the presence of hepatic glycogen and normal activity of glycogenolytic enzymes (phosphorylase, amylo-l,6-glucosidase, and glucose-6phosphatase) (Figure 5); infusions of fructose (Colle and Ulstrom, 1964) and glycerol (Senior and Loridan, 1969) result in a prompt increase in plasma blood glucose concentration, thus indicating normal activities of fructose-l,6-diphosphatase and glucose-6-phosphatase; plasma glycerol levels in the fed and fasted states are no different from those of similarly treated control children (Haymond, Karl and Pagliara, 1974), indicating that this substrate is not rate-limiting; responses to infusions of/3-hydroxybutyrate do not differ from those of normal children (Loridan and Senior, 1970); plasma insulin concentrations are appropriately low (Senior and Loridan, 1969; Grunt et al, 1970; Pagliara et al, 1972) and those of glucagon and cortisol are increased at the time of hypoglycaemia (Haymond, Karl and Pagliara, 1974). BEFORE DIET
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454
MOREY W. HAYMOND AND ANTHONY S. PAGLIARA
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neogenesis. Key enzymesare designated by number (1) glucose-6-phosphate,(2) glucokinase, (3) amylo-l,6-glucosidase, (4) phosphorylase, (5) phosphoglucomutase, (6) glycogen synthetase, (7) galactokinase, (8) galactose-1,-phosphate uridyl transferase, (9) uridine diphosphogalactose-4-epimerase,(10) phosphofructokinase, (11) fructose-l,6-diphosphatase, (12) fructose-l,6-diphosphatealdolase, (13) fructokinase, (14) fructose-l-phosphate aldolase; (15) phosphoenolpyruvatecarbodylase, (16) pyruvate carboxylase.From Pagliara et al (1973), with kind permission of the authors and the editor of Journal of Pediatrics. In these children, symptomatic hypoglycaemia and ketonaemia develop 8 to 16 hours following the initiation o f a hypocaloric ketogenic diet (1200 kcal per 1.73 m 2 body surface, 63 per cent fat, 17 per cent protein, 15 per cent carbohydrate) (Colle and Ulstrom, 1964). Normal children exhibit similar biochemical findings after 32 to 36 hours on the same dietary regimen, but do not develop symptomatic hypoglycaemia (Pagliara et al, 1972) (Figure 6). Comparable results have been obtained with fasting alone, thus indicating that the hypoglycaemia occurring during the ketogenic diet challenge is a consequence of its hypocaloric nature, rather than its fat content (Haymond, Karl and Pagliara, 1974) (Figure 7). Following an overnight fast, plasma glucose concentrations in children with ketotic hypoglycaemia are similar to age-matched normals. A provocative 24-hour fast (beginning after the evening meal) provides the advantage of inducing hypoglycaemia during the child's waking hour (16- 24 hours of fasting). Children with ketotic hypoglycaemia have normal venous lactate and pyruvate concentrations, but have hypoalaninaemia prior to and during either fasting or ketogenic diet challenge (Pagliara et al, 1972; Haymond,
KETOTIC HYPOGLYCAEMIA
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Karl and Pagliara, 1974) (Figures 6 and 7). The low plasma insulin and high FFA and ketone body concentrations virtually exclude hyperinsulinaemia as an aetiological factor (Colic and Ulstrom, 1964; Grunt et al, 1970; Loridan and Senior, 1970; Haymond, Karl and Pagliara, 1974). Glucocorticoid insufficiency can be excluded since plasma cortisol concentrations are higher in children with ketotic hypoglycaemia than those of normal children even prior to the development of fasting hypoglycaemia (Figure 8). In addition, tests of the pituitary adrenal axis are normal (Colle and Ulstrom, 1964; Senior and Loridan, 1969). No differences were observed in plasma growth hormone or glucagon in the ketotic hypoglycaemic children when compared with those of normal children until hypoglycaemia had ensued, at which time they appropriately increased (Figure 9). Infusion of alanine (250 mg/kg body weight) in these children produces a rise in plasma glucose ( A 15-25 mg/dl by min 15-30) without prominent changes in blood lactate, pyruvate or insulin concentrations (Pagliara et al, 1972; Haymond, Karl and Pagliara, 1974) (Figure 10). This response indicates that the entire gluconeogenic pathway from the level of pyruvate is intact, and hence a gluconeogenic enzyme defect can be excluded (Figure 5). Treatment with large doses of glucocorticoids prior to or during the administration of the ketogenic diet prevents the development of hypoglycaemia and ketosis (Colle and Ulstrom, 1964; Pagliara et al, 1972) (Figure 11). Within 4 to 6 hours of glucocorticoid administration, plasma alanine and glutamine concentrations increase two- to threefold (Pagliara
456
MOREY W. HAYMOND AND ANTHONY S. PAGLIARA
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et al, 1972). These results suggest that the protection from hypoglycaemia afforded by glucocorticoid therapy is a result of its acute catabolic effect on muscle protein, rather than induction of increased levels of hepatic gluconeogenic enzymes. POSSIBLE PATHOPHYSIOLOGICAL FACTORS CAUSING KETOTIC HYPOGLYCAEMIA The mechanisms responsible for the hypoalaninaemia and hypoglycaemia in these patients remains unknown. Since the major source of endogenous gluconeogenic amino acids is skeletal muscle, a defect in any of the enzymes or hormone-sensitive sites involved in protein catabolism, transamination, or amino acid efflux in this tissue might represent a potential aetiological basis for this disorder. On the other hand, in the original clinical description of this syndrome, it was pointed out that these children frequently are smaller than age-matched control subjects (Colle and Ulstrom, 1964; Grunt et al, 1970; Pagliara et al, 1972). Because of the increased glucose requirement on a per kg body weight basis in the young child, when compared with adults, any modest compromise in the supply of endogenous gluconeogenic substrates (e.g. amino acid from decreased muscle mass, independent of a specific enzyme or hormone defect) might predispose to the development of hypoglycaemia and ketosis. In this context, ketotic hypoglycaemia may
457
KETOTIC HYPOGLYCAEMIA
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constitute one end o f a spectrum representing the normal distribution pattern of tolerance to fasting (Senior, 1973). In all previous studies with ketotic hypoglycaemic children, plasma concentrations have been the index of gluconeogenic availability. Without measurements of the rates o f alanine appearance and disappearance, as well as conversion rates of potential gluconeogenic substrates to glucose during the evolution of hypoglycaemia, the hypothesis that the hypoglycaemia is substrate limitation remains to be proved. Following an overnight fast and at a time when the plasma concentrations of glucose are normal, the rates of glucose flux were similar between normal children and those with ketotic hypoglycaemia. In contrast, rates of alanine production in ketotic hypoglycaemic children were lower than normals (Table 2), which is consistent with the postulate of substrate limitation. The contribution o f alanine to hepatic glucose production in the adult in the postabsorptive state is approximately 2 to 4 per cent (Clarke et al, 1979), but may be significantly higher with prolonged fasting (Cahill, 1970). The contribution of alanine and other 'potential' gluconeogenic amino acids to hepatic glucose production in children is unknown. In children and particularly the child with ketotic hypoglycaemia, plasma substrate and hormonal concentrations during short-term fasts are consistent with a more accelerated state o f fasting, as compared to c o m p a r a b l y fasted adults (Figures 1, 2 and 7). When the total plasma concentration o f 18-acid neutral
458
MOREY W. H A Y M O N D AND A N T H O N Y S. P A G L I A R A
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amino acids was measured, there was a significant decrease in the plasma concentration of 'potential' total gluconeogenic amino acids in the ketotic hypoglycaemic children throughout the fast, which was lower than those of similarly fasted children (Haymond, Karl and Pagliara, 1974). If one could project from the alanine turnover studies cited above (Table 2), substrate limitation in the form of gluconeogenic amino acid deficiency could result in a small decrease in glucose production which, if persistent throughout the fast, could account for the hypoglycaemia seen in this disorder. Confirmation of this hypothesis awaits further turnover studies in these children. The rapid development of ketosis in children, when compared with adults (Figure 2), is temporarily associated with the fall in both plasma concentrations of glucose and insulin. This propensity to develop ketosis is further accentuated in the child with ketotic hypoglycaemia (Figure 7). Since ketone
459
KETOTIC HYPOGLYCAEMIA i.v. Alonlne 250 mg/kg
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Figure 11. Response to the provocative ketogenic diet with and without cortisone acetate administration. Patient D.C. underwent two challenges with the ketogenic diet. Oral cortisone acetate 40 mg every six hours for three doses was administered during the second challenge. The response to intravenous glucagon 0.03 mg/kg body weight is shown at the bottom of the figure, 18 hours after the first, and 24 hours after the second challenge. From Pagliara et al (1972), with kind permission of the editor of Journal of Clinical Investigation.
460
MOREY W. H A Y M O N D AND A N T H O N Y S. P A G L I A R A
Table 2. Rates o f glucose and alanine f l u x in normal children and patients with ketotic
hypoglycaemia after an overnight fast
Normal children ( N = 8 ) Ketotic hypoglycaemic children (N = 10)
Glucose fluxa /~mol/kg/min
Alanine flux b /~mol/kg/min
32 _+ 9 34 +_ 3
15 _+ 2 9 _+ 1
aDetermined utilizing a constant in fusion of D [6,6-2 H 2] glucose. bDetermined utilizing a constant infusion of L-[2,3,3,3-2H4] alanine and venous blood sampling.
bodies are insulin secretogogues in man (Miles, Haymond and Gerich, 1980), it is possible that the hyperketonaemia in normal and ketotic hypoglycaemic children could stimulate small increases in portal insulin concentrations, which could result in decreased hepatic glucose production without affecting peripheral plasma insulin concentrations. The accelerated ketosis seen in children as compared with adults is most likely due to increased rates of production. The hyperketonaemia may be important in the maintenance of glucose homeostasis during fasting since ketones can be utilized by brain, thus decreasing obligate glucose requirements (Owen et al, 1967). In the children with ketotic hypoglycaemia, the higher plasma ketone body concentrations could be a result of heightened ketone body production as compared to normal, or alternatively a decrease in ketone body utilization. If such a decrease in utilization were at the level of the central nervous system, glucose would be primarily utilized resulting in an accelerated rate of glucsoe utilization during the evolution of hypoglycaemia which outstrips the child's total capacity to produce glucose. This could account for the accelerated changes in the circulating concentrations of metabolic fuels and hormones observed with fasting or with ketogenic diet provocation in this disorder. Until measurements of rates of production and utilization of glucose, alanine, ketone bodies and of plasma C-peptide concentrations have been performed during the evolution of the hypoglycaemia in this disorder, it cannot be determined which, if any, of the possibilities discussed above are involved in the pathophysiology of this disorder. Some studies have implicated abnormal adrenal medullary response in children with ketotic hypoglycaemia. Decreased urinary catecholamine excretion has been documented in these children in response to insulin, 2-deoxyglucose and the ketogenic diet (Broberger and Zetterstrom, 1961; Koffler, Shubert and Hug, 1971), as well as abnormally low plasma epinephrine concentration during insulin-induced hypoglycaemia (Christensen, 1974). The pathophysiological role that epinephrine insufficiency may play in the hypoglycaemia and hypoalaninaemia in this disorder remain to be elucidated since adrenalectomized adults recover normally from insulin-induced hypoglycaemia, provided glucagon secretion is intact (Cryer, 1981). Whatever the cause, it would seem reasonable to propose that the underlying deficit is present from birth, but is not manifested until the child
KETOTIC HYPOGLYCAEMIA
461
encounters a catabolic stress such as infection or periods of caloric restriction. Furthermore, as the supply of endogenous substrate increases relative to glucose d e m a n d (i.e. with age), one might expect spontaneous remission to occur. M A N A G E M E N T OF C H I L D R E N W I T H K E T O T I C HYPOGLYCAEMIA Ketotic hypoglycaemia is a self-limited disorder that predictably remits by 8- 9 years o f age. The hypoglycaemia usually occurs in association with intercurrent infections, or during periods in which caloric restriction is sustained for 12 hours or more. Treatment consists of frequent feeding (4 - 5 meals per day) o f a high protein, high carbohydrate diet (Colle and Ulstrom, 1964). Parents should be instructed to test the child's urine for ketones during periods o f illness, since ketonuria usually precedes hypoglycaemia by several hours. Under these circumstances, oral or parenteral glucose should be administered to prevent the development of hypoglycaemia. SUMMARY
Ketotic hypoglycaemia is the most c o m m o n f o r m of childhood hypoglycaemia. This disorder classically manifests itself between the ages of 18 months and 5 years, and generally remits spontaneously before 8 or 9 years of age. A presumptive diagnosis is made by documenting a low blood sugar in association with ketonuria, ketonaemia and typical s y m p t o m s of hypoglycaemia. The definitive diagnosis is established by demonstrating an inability to tolerate a provocative ketogenic diet, or a fast. Susceptible or affected children develop severe hypoglycaemia and ketosis on this diet within 24 hours. Plasma alanine concentrations on either a normal or ketogenic diet were significantly lower in ketotic hypoglycaemic children c o m p a r e d with normal children. In contrast to adults, even normal children develop hypoglycaemia and ketonaemia when calorically deprived for relatively short periods o f time (32 to 36 hrs). ACKNOWLEDGEMENTS
The authors were supported in part by the Mayo and Wasie foundations and USPHS AM-26989, and Gunderson Medical Foundation Ltd, with funds from the Trane Foundation, respectively.
REFERENCES
Bier, D. M., Leake, R. D., Arnold, K. J. et al (1977) Measurement of 'true' glucose production rates with 6,6-dideuterioglucose. Diabetes, 26, 1016-1023. Broberger, O. & Zetterstrom, R. (1961) Hypoglycemia with an inability to increase the epinephrine secretion in insulin-induced hypoglycemia.Journal of Pediatrics, 59, 215-222. Cahill, G. H., Jr (1970) Starvation in man. New England Journal of Medicine, 282, 668.
462
MOREY W. HAYMOND AND ANTHONY S. PAGLIARA
Cahill, G. F., Jr, Herrera, M. G., Morgan, A. P. et al (1966) Hormone fuel interrelationships during fasting. Journal of Clinical Investigation, 45, 1751. Chaussain, J. L., Georges, P., Olive, G. et al (1974) Glycemic response to 24-hour fast in normal children and children with ketotic hypoglycemia II: Hormonal and metabolic changes. Journal of Pediatrics, 85, 776-781. Chaussain, J. L., Georges, P., Calzada, L. et al (1977) Glycemic response to 24-hour fast in normal children. III. Influence of age. Journal of Pediatrics, 91, 711-714. Christeusen, N. J. (1974) Hypoadrenalinemia during insulin hypoglycemia in children with ketotic hypoglycemia. Journal of Clinical Endocrinology and Metabolism, 38, 107-112. Clarke, W. L., Santiago, J. V., Thomas, L. et al (1979) Adrenergic mechanisms in recovery from hypoglycemia in man: Adrenergic blockage. American Journal of Physiology, 236, E149-E152. Cochrane, W. A., Payne, W. W., Simpkiss, M. J. & Woolf, L. I. (1956) Familial hypoglycemia precipitated by amino acids. Journal of Clinical Investigation, 35, 411-422. Colle, E. & Ulstrom, R. A. (1964) Ketotic hypoglycemia. Journal of Pediatrics, 64, 632-651. Cornblath, M. & Schwartz, R. (1976) Disorders of Carbohydrate Metabolism in Infancy. 2rid edition, Philadelphia: W. B. Saunders. Cryer, P. E. (1981) Glucose counterregulation in man. Diabetes, 30, 261-264. Grunt, J. A., McGarry, M. E., McCollum, A. T. & Gould, J. B. (1970) Studies of children with ketotic hypoglycemia. Yale Journal of Biological Medicine, 42, 420-438. Haymond, M. W., Karl, I. E., Pagliara, A. S. (1974) Ketotic hypoglycemia: An amino acid substrate limited disorder. Journal of Clinical Endocrinology and Metabolism, 38, 521-530. Haymond, M. W., Strobel, K., Galim, B. & DeVivo, D. (1978) Effects of ketosis on glucose and alanine fluxes in children. Clinical Research, 25, 682A. Haymond, M. W., Karl, E., Clarke, W. L. et al (1982) Differences in circulating gluconeogenic substrates during short-term fasting in men, women and children. Metabolism, 31, 33-42. Koffler, H., Schubert, W. K. & Hug, G. (1971) Sporadic hypoglycemia: Abnormal epinephrine response to the ketogenic diet or to insulin. Journal of Pediatrics, 78, 448-453. Kogut, M. D., Blaskovics, M. & Donnell, G. N. (1969) Idiopathic hypoglycemia: A study of twenty-six children. Journal of Pediatrics, 74, 853-871. Loridan, L. & Senior, B. (1970) Effects of infusion of ketones in children with ketotic hypoglycemia. Journal of Pediatrics, 76, 69-74. McQuarrie, I., Bell, E. T., Zimmerman, B. & Wright, W. S. (1954) Deficiency of alpha cells of pancreas as possible etiological factor in familial hypoglycemia. Federation Proceedings, 9, 337. Miles, J. M., Haymond, M. W. & Gerich, J. E. (1980) Suppression of glucose production and stimulation of insulin secretion by physiological concentrations of ketone bodies in man. Journal of Clinical Endocrinology and Metabolism, 52, 34-37. Owen, O. E., Morgan, A. P., Kemp, H. G. et al (1967) Brain metabolism during fasting. Journal of Clinical Investigation, 46, 1589-1597. Pagliara, A. S., Karl, I. E., DeVivo, D. C. et al (1972) Hypoalaninemia: A concomitant of ketotic hypoglycemia. Journal of Clinical Investigation, 51, 1440-1449. Pagliara, A. S., Karl I. E., Haymond, M. W. & Kipnis, D. M. (1973) Hypoglycemia in infancy and childhood. Parts I and II. Journal of Pediatrics, 82, 365-379, 558-577. Senior, B. (1973) Ketotic hypoglycemia. Journal of Pediatrics, 82, 555-556. Senior, B. & Loridan, L. (1969) Gluconeogenesis and insulin in the ketotic variety of childhood hypoglycemia and in control children. Journal of Pediatrics, 74, 529-539. Sizonenko, P. C., Paunier, L., Vallotton, J. B. et al (1973) Response to 2-Deoxy-D-glucose and to glucagon in ketotic hypoglycemia of childhood. Evidence for epinephrine deficiency and altered alanine availability. Pediatric Research, 7, 983-993.