Hypoglycaemia in the infant and child

8 Hypoglycaemia in the infant and child J. W . G R E G O R Y A. AYNSLEY-GREEN

INTRODUCTION It has long been recognized that babies and young children have differing glucose homeostasis from adults (Spence, 1921). The symptoms and signs due to hypoglycaemia in infancy were first described in 1937 by Hartman and Jaudon, and thereafter the permanent neurological sequelae of untreated hypoglycaemia were recognized (McQuarrie, 1954; Brown and Wallis, 1963). Further research elucidated the importance of intrauterine factors and the vulnerability of neonates to hypoglycaemia (Farquhar, 1954; Komrower, 1954; Cornblath et al, 1959; Neligan et al, 1963). The homeostatic mechanisms for the control of blood glucose levels in fed and fasting states are shown in Figure 1 and are discussed further in Chapter 1. The young child differs from an adult in that glycogen stores are only adequate for a period of starvation of approximately 12 h (as discussed in Chapter 8, tolerance of starvation is even more limited in the neonatal period) and thereafter glucose homeostasis is dependent on gluconeogenesis (Chapter 1, Figure 5). Therefore, infants and young children are more vulnerable than adults to hypoglycaemia; children are unable to tolerate such prolonged periods of starvation (Chaussain, 1973; Haymond et al, 1982) and hypoglycaemia may occur more frequently as a consequence of relatively impaired availability of gluconeogenic substrates (Haymond et al, 1982). Ketogenesis, however, is much more rapid and occurs to a higher level in children than in adults (Haymond et al, 1982). A further predisposing factor to hypoglycaemia in childhood is that glucose production rates appear to be increased to meet the metabolic demands of a brain that, relative to body size, is much larger than in adults (Senior and Loridan, 1969; Bier et al, 1977). In this chapter, we highlight the ways in which hypoglycaemia may present clinically and the principles of the management in infancy and childhood, with particular reference to common causes of hypoglycaemia and to those causes such as hyperinsulinism in which recent significant therapeutic advances have been made. It is impossible in a chapter of this size to provide a comprehensive review of all causes of hypoglycaemia in infancy and childhood, and for further information the reader is referred to other extensive reviews of hypoglycaemia (Cornblath and Schwartz, 1991) and inherited inborn errors of metabolism (Scriver et al, 1989). Bailli~re' s Clinical Endocrinology and Metabolism--

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Figure 1. The control of blood glucose concentrations in (a) the fed state and (b) the fasted state. CLINICAL PRESENTATION In paediatric practice, hypoglycaemia in infancy and childhood most commonly occurs in the neonatal period (Chapter 7). Later in childhood, it

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more frequently presents in situations where catabolism is occurring and the counterregulatory responses are being induced. This may happen, for example, during periods of relative starvation associated with changes in the feeding pattern, such as occur when the night-time feed is first omitted in infancy, during fasting for religious purposes (Senior, 1973), whilst a child is being prepared for surgery (O'Flynn and Milford, 1989), or in association with intercurrent illness such as gastroenteritis (Zuppinger, 1975) that produces a physiological stress leading to a catabolic state. Pharmacologically induced hypoglycaemia may also present therapeutic problems in childhood, particularly in association with provocation tests used to assess anterior pituitary function, in relation to insulin-dependent diabetes mellitus (see Chapter 11) and as a consequence of 'Munchausen syndrome by proxy' (Dershewitz et al, 1976; Teale et al, 1989). The true incidence of hypoglycaemia in childhood after the neonatal period is unknown. It is thought to account for approximately 2 to 3 per 1000 hospital admissions (Zuppinger, 1975). Clinical recognition of hypoglycaemia is complicated by the non-specific nature of most of the symptoms and signs of hypoglycaemia and by the episodic nature of its presentation. The symptoms of hypoglycaemia can be divided into those related to the autonomic and those caused by the neuroglycopenic effects of hypoglycaemia (Table 1). The autonomic effects of hypoglycaemia are mainly caused by increased adrenaline secretion and are likely to occur at higher blood glucose concentrations and therefore in advance of the symptoms due to neuroglycopenia (Mitrakou et al, 1991). Table 1. Symptoms of hypoglycaemia in infancy

and childhood. Autonomic

Neuroglycopenic

Anxiety Palpitations Pallor Sweating Irritability Tremor

Hunger and abdominal pain Nausea and vomiting Dizziness Tingling Headache Blurred vision Mental confusion Unusual behaviour Weakness and lassitude Faintness Coma Convulsions

CLINICAL ASSESSMENT When an infant or child presents with symptoms suggestive of hypoglycaemia, a detailed case history and physical examination are essential. Furthermore, to investigate the aetiology of the hypoglycaemia, it is critically important at the time of the hypoglycaemic symptoms to remove a sample of blood for biochemical investigations before administration of glucose and to obtain the next urine sample that is passed.

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The case history should include details of the pregnancy such as the presence of maternal diabetes mellitus, which may predispose to transient hyperinsulinism in the newborn. The mode and nature of delivery and the birth weight should be recorded. Breech delivery may predispose the infant to an increased risk of hypopituitarism and a disproportionately increased birth weight may be the presenting feature of nesidioblastosis. A detailed feeding history, particularly in cases presenting in infancy, is important as are the temporal relationship of the symptoms to feeding or fasting and to changes in feeding pattern. Symptoms that occur when calorie intake appears to be excessive may suggest the presence of hyperinsulinism, whereas the occurrence of symptoms in the presence of either lactose or fructose and sucrose may suggest the presence of galactosaemia or disorders of fructose metabolism, respectively. The maximum length of time that the subject has fasted without adverse sequelae should be recorded. Systematic enquiry should elicit other symptoms suggestive of coexistent illnesses that may result in a catabolic state predisposing to hypoglycaemia, particularly as may occur in inborn errors of fat and protein metabolism. A social history is relevant because occasionally hypoglycaemia may be the presenting symptom of accidental ingestion or factitious illness secondary to the administration of insulin or oral hypoglycaemic agents by a parent or close family contact (Dershewitz et al, 1976). Finally, a family history must be established to elicit the presence of consanguinity in the parents or episodes of unexplained metabolic acidosis or cot-death in siblings that may be associated with the presence of an inherited autosomal recessive inborn error of metabolism. On physical examination, basic anthropometric data must be recorded on appropriate growth charts. An infant who is underweight may have limited glycogen reserves, whereas excessive weight, height or height velocity may be a feature of hyperinsulinism. Short stature in older children, especially when associated with microgenitalia in boys, may suggest hypopituitarism. The presence of dysmorphic features should be looked for, such as abnormal ear lobe creases, macroglossia, umbilical herniae and hemihypertrophy, which are features of the Beckwith-Wiedemann syndrome. Cranial midline defects such as a cleft palate or the presence of optic atrophy are both features that may suggest the presence of hypopituitarism. The skin and mouth should be inspected for the increased pigmentation associated with Addison's disease and finally the abdomen should be examined for evidence of hepatosplenomegaly, which occurs in disorders of glycogen metabolism. Despite the existence of the signs described above, it should be borne in mind that many of the causes of hypoglycaemia may not be associated with the presence of any abnormal physical findings. In summary, a careful case history and physical examination may provide clues to the cause of hypoglycaemia. INVESTIGATIONS Whereas a detailed history and examination may have to wait until after

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initial therapeutic steps have been taken to reverse the hypoglycaemia, it is very important for diagnostic purposes to obtain a sample of blood for investigations prior to administration of glucose, together with an aliquot of the next urine passed (even if urine is not produced until some time after the administration of glucose). Blood samples at the time of hypoglycaemia are necessary for retrospective confirmation of the presence of hypoglycaemia and for the interpretation of the blood glucose concentration in the context of the concurrent concentrations of other metabolic fuels and hormones. The protocol for the practical investigation of hypoglycaemia in our unit is described below. Further details of the principles behind these tests and the analytical methodology are to be found in Chapters 3 and 6, respectively. It is usually appropriate, first, to ascertain whether the symptoms are indeed related to the possibility of hypoglycaemia by taking blood from a finger prick for immediate assessment by a bedside method such as Dextrostix or BM stix testing. If the capillary blood glucose is less than 2.6 mmol/l or (in view of the potential inaccuracy of the methods available for bedside testing when blood glucose values are within the hypoglycaemic range; Cornblath and Schwartz, 1991) the patient has symptoms suggestive of hypoglycaemia, an intravenous cannula is inserted into the patient. From this, the following samples are taken, preferably without venestasis occurring: (a) (b) (c) (d) (e)

1-2 ml of blood in fluoride oxalate for laboratory confirmation of the blood glucose concentration. 2 ml of blood in a plain tube for estimation of the serum urea and electrolyte (including bicarbonate) concentrations and liver function tests. 4 ml of blood into lithium heparin for analysis of plasma non-esterified fatty acid, insulin, growth hormone and cortisol concentrations. 0.5 ml of blood into perchloric acid for the measurement of intermediary metabolite concentrations (lactate, pyruvate, [3-hydroxybutyrate, acetoacetate, glycerol, alanine). The next urine specimen produced by the patient should be collected for estimation of urinary ketones, reducing substances (galactose and fructose), dicarboxylic acids, glycine conjugates and carnitine derivatives.

Whereas blood sampling at the time of the hypoglycaemic episode for all of the above investigations may not be practical, at the minimum, assays of blood glucose, plasma insulin, cortisol and free fatty acids and urinary ketone bodies should be undertaken (Soltesz and Aynsley-Green, 1992). Samples should also be stored, to be dispatched later for further analyses as appropriate at a referral centre with adequate laboratory facilities and expertise. Once blood samples have been removed, hypoglycaemia may be reversed with intravenous glucose as described below. The next urine specimen should still be collected for analysis when it is produced, even if treatment has taken place. If the symptoms of hypoglycaemia have a clear temporal relationship with feeding or fasting, it is then usually appropriate to proceed to formal elective

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investigation of the 24-h metabolic profile in which intermediary metabolites are measured before and 1 h after each main meal, followed by a starvation test (Chapter 3). Finally, dependent on the outcome of these biochemical investigations (see below), it may be necessary to proceed to specific stimulation tests (e.g. glucagon provocation to assess mobilization of glycogen reserves, or other specific endocrine provocation tests to assess steroid or growth hormone secretion). These and other investigations including those utilizing stable isotopes to estimate the rate of gluconeogenesis are discussed in more detail in Chapter 3.

Interpretation of the results of investigations In the presence of hypoglycaemia, interpretation of the interrelationship of metabolites and hormones is dependent on them having been taken at the same time. Elevated levels of both ketone bodies and non-esterified fatty acids imply mobilization of fat stores that occurs when insulin secretion is switched off. This was formerly described as 'ketotic hypoglycaemia' and is the finding in accelerated starvation, cortisol and growth hormone deficiencies, and in inborn errors of metabolism in which glucose production is decreased but lipolysis is unaffected (e.g. glycogen synthetase deficiency). In these circumstances, estimation of hormone concentrations should provide the diagnosis, and in the presence of significant hypoglycaemia a subnormal cortisol or growth hormone response is highly significant (Aynsley-Green et al, 1991). If, however, ketone bodies and non-esterified fatty acid concentrations are both low, this implies decreased mobilization of fat stores as occurs in the presence of hyperinsulinism. Elevated non-esterified fatty acid concentrations and simultaneously decreased ketone bodies in the presence of low insulin levels suggest a disorder of fatty acid metabolism. Elevated concentrations of blood lactate, pyruvate, alanine or glycerol suggest disorders of gluconeogenesis, glycogenolysis or glycolysis. AETIOLOGY AND TREATMENT OF HYPOGLYCAEMIA

General principles of therapy Once the initial blood sample has been removed for investigations, it is important to treat hypoglycaemia and prevent further deterioration or permanent neurological damage. At first presentation in hospital, the precise diagnosis will probably be unknown and it is our practice to give 0.2-0.4g of glucose per kg body weight as an intravenous bolus over 4-6 min, followed by an infusion of glucose at a rate of 6 mg/kg body weight per min. The use of an intravenous infusion of glucose rather than intermittent pulses of concentrated and hyperosmolar glucose is necessary to prevent the risk of cerebral oedema (Shah et al, 1992). This rate of glucose infusion is sufficient to reverse catabolism in normal circumstances but may be inadequate to reverse hypoglycaemia due to hyperinsulinism. In these

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circumstances, rates of glucose disposal may be dramatically increased and rates of glucose infusion up to 25 mg/kg body weight per rain may be necessary. Other specific therapeutic manoeuvres for prevention and treatment of hypoglycaemia due to differing specific causes will be discussed in detail in the sections below. In addition, an excellent review of the recommendations for the avoidance of and treatment of hypoglycaemia during intercurrent illness in patients with inborn errors of intermediary metabolism has recently been published (Dixon and Leonard, 1992).

Hypoglycaemia due to hyperinsulinism

Persistent hyperinsulinism Hyperinsulinism is the most common cause of intractable hypoglycaemia beyond the neonatal period (LaFranchi, 1987). In this condition, hypoglycaemia is due to a combination of increased glucose utilization and decreased glucose production. Under the age of 1 year, the cause is most likely to be a diffuse pancreatic pathology such as nesidioblastosis or [3-cell hyperplasia, whereas in older children a discrete pathology such as a pancreatic islet cell adenoma is more likely. Persistent hyperinsulinaemic hypoglycaemia of infancy frequently presents with severe and intractable hypoglycaemia within minutes of birth. These infants often resemble in appearance the infants of a diabetic mother, being macrosomic with increased adiposity, suggesting prenatal hyperinsulinism. Clinical features suggestive of the Beckwith-Wiedemann syndrome may also be present. In older children who may have pancreatic islet cell adenomata, the presenting picture is more commonly that of progressively increasingly severe neurological and autonomic sequelae of episodic hypoglycaemia, occasionally associated with tall stature and obesity. In infancy, the pancreatic histological findings in cases of persistent hyperinsulinaemic hypoglycaemia are the subject of some controversy (Rahier et al, 1984). Whereas focal lesions may be found on pancreatic histological examination in a small proportion of infants with persistent hyperinsulinism, nesidioblastosis is not a specific feature of infants with hypoglycaemia, being observed also in age-matched controls dying of nonhypoglycaemic related illnesses (Rahier et al, 1984). The same group has suggested that affected infants demonstrate increased B-cell nuclear size, reflecting enhanced functional activity of these ceils. Conversely, some children with proven hyperinsulinism have no abnormality of the endocrine pancreas, though in vitro studies of pancreatic tissue may show evidence of abnormal insulin kinetics (Aynsley-Green and Soltesz, 1985). Nevertheless, review of the histological findings in cases of persistent hyperinsulinism or islet cell dysregulation syndrome demonstrates the presence in the majority of cases of an increased total pancreatic endocrine mass, with ductoinsular proliferation and development of discrete endocrine cells from ductal epithelium, together with decreased numbers of somatostatin cells and a loss of normal insulin and somatostatin cell ratio and contact (Aynsley-Green and Soltesz, 1985).

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Biochemical diagnosis (which will not distinguish between the differing aetiologies of hyperinsulinism) is dependent on the demonstration of an inappropriately elevated plasma insulin for glucose concentration. During fasting in healthy infants, plasma insulin levels normally fall to less than 5-10 mU/1, and insulin levels of this order or above in the presence of hypoglycaemia are abnormal. Indirect evidence of hyperinsulinism includes the presence of very low or almost undetectable blood ketone body levels and low branched-chain amino acid, non-esterified fatty acid and glycerol levels during hypoglycaemia due to the inhibition of fat metabolism (Berger et al, 1978; Chaussain et al, 1980; Soltesz et al, 1980; Aynsley-Green et al, 1981b). Furthermore, the required glucose infusion rates to correct the hypoglycaemia are usually greater than normal, though hypoglycaemia may respond to both glucagon and somatostatin. Further investigations should include pancreatic ultrasound or abdominal CT scan, which may help in delineating a pancreatic adenoma, though frequently these investigations are unhelpful (Spitz et al, 1992). Prompt treatment of persistent hyperinsulinaemic hypoglycaemia of infancy is necessary to prevent the risk of long-term adverse neurological sequelae (Aynsley-Green et al, 1981b). Initially, this requires a glucose infusion, often at rates in excess of 6-9 mg/kg body weight per min and occasionally as high as 25 mg/kg body weight per min (Aynsley-Green et al, 1981b). Secure venous access is important and the insertion of central lines may be necessary, especially when concentrated glucose infusions are necessary. When excessive glucose infusion rates are required, additional pharmacological therapy should be considered. Initially, diazoxide (Drash and Wolff, 1964; Cornblath and Schwartz, 1991) may be used in doses up to 25mg/kg per day in three divided doses at 8-h intervals. Diazoxide suppresses insulin secretion, and increases adrenaline secretion and gluconeogenesis (Aynsley-Green, 1988). Its effect may be potentiated by the addition of a thiazide diuretic such as chlorothiazide (Aynsley-Green and Soltesz, 1985). Complications of diazoxide therapy include hypertrichosis of the lanugo type, which in long-term therapy may be used as an indirect marker of compliance, fluid retention, cardiac failure (Abu-Osba et al, 1989) and ataxia (McGraw and Price, 1985). Unfortunately, the beneficial effects of diazoxide are frequently transient and alternative treatment with a long-acting somatostatin analogue (Sandostatin) or surgery may need to be considered. Natural-sequence somatostatin is known to suppress insulin secretion but, because of its short half-life, requires to be given as a continuous intravenous infusion (Hirsch et al, 1977). Recent work (Kirk et al, 1988) has demonstrated that subcutaneous somatostatin analogue at a dose of 10-40 ~g/kg per day (Glaser et al, 1989) is effective in the short-term management of hypoglycaemia due to hyperinsulinism and may be of value when venous access is problematical or for pre- and intraoperative stabilization (Jackson et al, 1987). However, the use of somatostatin and its analogue may not be without potential problems. Tachyphylaxis to somatostatin analogue has been reported to develop rapidly (Hawdon et al, 1990). Somatostatin analogue is also known to increase mouth-to-caecum transit time, to alter

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pancreatic exocrine function and almost abolish cholecystokinin release and gallbladder contraction (Lembcke et al, 1987). There is also concern about the effects of somatostatin on growth hormone, thyroid hormone, corticosteroids and gut hormones in young infants (Aynsley-Green et al, 1981a) and there is evidence of a growth-hormone-suppressing effect of long-term somatostatin analogue (Jackson et al, 1988). Despite these reported problems, there is increasing evidence that prolonged courses of therapy may be used without major side-effects (Delemarre-van de Waal et al, 1987; Wilson et al, 1988; DeClue et al, 1990; Glaser and Landaw, 1990), though subtotal pancreatectomy remains the treatment of choice for nesidioblastosis, particularly in patients not responding to optimal medical therapy. The preferred surgical treatment is early referral for a 95% pancreatectomy. Less radical resections may result in a recurrence of the hypoglycaemia (Spitz et al, 1992). Steatorrhoea, hyperglycaemia necessitating insulin therapy, or recurrent hypoglycaemia are not uncommon in the immediate postoperative period (Thomas et al, 1977; Gough, 1984) but these problems usually resolve in the first few months (Dunger et al, 1988; Spitz et al, 1992). Histological examination of the pancreas in cases of nesidioblastosis is discussed previously; the coexistent presence of an adenoma is also recognized (Aynsley-Green et al, 1981b). Most cases respond satisfactorily to 95% pancreatectomy, but occasionally hypoglycaemia reoccurs. Such children should be restarted on diazoxide or somatostatin analogue, but if this fails to produce normoglycaemia then total pancreatectomy may be required. To ensure that the pancreas is entirely removed, duodenal and biliary reanastomosis may be necessary (Aynsley-Green, 1988). Insulin tolerance tests

Anterior pituitary function testing using insulin provocation has long been used as the 'gold standard' to assess the integrity of the pituitary adrenal axis and to assess growth hormone secretory reserve (Fish et al, 1986). The test relies on insulin-induced hypoglycaemia as a secretagogue of adrenocorticotrophic and growth hormones. Deaths have been reported in children undergoing this test, due to cerebral oedema secondary to excess hyperosmolar fluid administration in the form of 50% dextrose given to reverse the symptoms of hypoglycaemia (Shah et al, 1992). As a consequence, the following is recommended: 1.

Insulin provocation testing should only be undertaken in units with specialist experience of this test. 2. If the subject to be tested is suspected of having hypopituitarism, 0.05 units of insulin per kg body weight rather than the conventional dose of 0.1 units per kg should be administered initially. 3. A secure indwelling venous cannula should be in place and a doctor should be present at all times. 4. If severe hypoglycaemia occurs, it should be corrected with 200 mg/kg (10% dextrose, 2 ml/kg) given over 4--6 rain.

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If hypoglycaemia (BM stix less than 2.6mmol/1) persists, a glucose infusion of 10 mg/kg per min should be started. If hypoglycaemia is reversed, further glucose intravenously should not be given, but if there is no improvement in the conscious level after several minutes an alternative explanation should be sought. If hypopituitarism is suspected 100 mg of hydrocortisone should be given intravenously.

It should also be noted that similar problems may occur with rebound hypoglycaemia following glucagon provocation testing and the principles of management remain the same (Shah et al, 1992).

Other causes of hyperinsulinism Pluriglandular syndrome. This rare condition of childhood is biochemically indistinguishable from other causes of hyperinsulinism and is a hyperplastic or neoplastic condition of the pancreatic islet cells in association with pituitary and parathyroid involvement (Underwood and Jacobs, 1963; Clarke et al, 1972).

Autoimmune hypoglycaemia. Autoimmune hypoglycaemia is associated with elevated plasma insulin levels, detectable insulin antibodies without a previous history of exogenous insulin therapy, and impaired glucose tolerance. This condition is unusual in childhood (Goldman et al, 1979; Meschi et al, 1992; Rovira et al, 1982) but may resolve spontaneously or respond to steroid therapy (Meschi et al, 1992).

Factitious hypoglycaemia. Factitious hyperinsulinism may be a manifestation of 'Munchausen syndrome by proxy' (Meadow, 1977) and may result from injections of insulin or from other drugs that induce insulin secretion such as the sulphonylureas (Dershewitz et al, 1976). Exogenous insulin administration is recognized by the presence of hypoglycaemia that is often unrelated to periods of starvation or exercise. Biochemical investigations will demonstrate hyperinsulinism but low plasma C-peptide levels, though if sulphonylurea abuse is the cause then C-peptide or proinsulin levels will be normal or high (Teale et al, 1989). After initial treatment of the hypoglycaemia, relatively small doses of glucose are required to maintain euglycaemia. Management of this situation requires that the safety of the child be guaranteed and confrontation of the abuser with the diagnosis is required. Long-term management usually involves a multidisciplinary approach with appropriate social and psychiatric support for the family or, where the child's future safety appears to be in jeopardy, removal of the child from the family into an alternative environment such as foster care. Hypoglycaemia due to decreased glucose production

Accelerated starvation Accelerated starvation is largely a diagnosis of exclusion and is the most common cause of hypoglycaemia in the older child. Its aetiology is not

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clearly understood but, characteristically, children present with this disorder between the ages of 1 and 5 years. They are usually small, with decreased muscle bulk and glycogen stores and a large organ-to-bodyweight ratio. There is often a preceding history of intrauterine growth retardation and neonatal hypoglycaemia. It is thought that this condition is due to a combination of decreased glucose production due to a limitation of amino acid substrates (Haymond et al, 1982) and to the presence of increased glucose utilization (Kerr et al, 1981; Aynsley-Green and Soltesz, 1985), though alternative evidence suggests that adrenomedullary hyporesponsiveness may have an aetiological role (Christensen, 1974). It is probable that accelerated starvation merely represents one end of the spectrum of responses to starvation (Senior, 1973) as healthy children show a similar metabolic response to fasting for 24-36 h as shown by affected children after 8-16 h. Patients with this disorder typically present with a history of hypoglycaemia occurring the morning after episodes of unusually intense exercise or in the presence of intercurrent illness. Biochemical investigations in the presence of hypoglycaemia show substantially raised blood ketone bodies, low plasma alanine and normal blood pyruvate and lactate levels (Pagliara et al, 1972). There should be evidence of a normal counterregulatory endocrine response with very low plasma insulin levels and no evidence of a hormonal insufficiency or liver disease (Senior and Loridan, 1969). In the fed state, the glycaemic response to glucagon is normal, but when hypoglycaemia is present there is no response to glucagon (Colle and Ulstrom, 1964). Treatment primarily involves educating the parents about the risks to their child of prolonged periods of fasting. Regular, frequent high-protein, high-carbohydrate feeds are necessary and parents should be taught to test urine for ketones during intercurrent illnesses. The presence of ketones indicates the need for glucose therapy. Most children with accelerated starvation appear to outgrow the disorder by adolescence.

Endocrine insufficiency

Pituitary hormone deficiencies During hypoglycaemia, the presence of both an inadequate growth hormone and cortisol response may suggest panhypopituitarism. Both growth hormone and cortisol stimulate hepatic gluconeogenesis. Growth hormone also stimulates lipolysis, whereas cortisol increases protein breakdown to provide alternative substrates for gluconeogenesis. Congenital hypopituitarism often presents in the first few days of life with physical signs suggesting multiple pituitary hormone deficiencies (e.g. hypoglycaemia, jaundice, microgenitalia). Isolated growth hormone insufficiencyor acquired panhypopituitarism that is often idiopathic or may occur in the presence of tumours such as a craniopharyngioma more usually present at an older age with the onset of symptoms over a longer time period (e.g. growth failure and non-specific symptoms of ill-health). The frequency of hypoglycaemia in

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children with either isolated growth hormone or multiple anterior pituitary hormone deficiencies has been reported to range from 11% to 27% (Brasel et al, 1965; Hopwood et al, 1975). In common with many other causes of hypoglycaemia, the incidence of hypoglycaemia with growth hormone insufficiency decreases with increasing age (Wolfsdoff et al, 1983). At the time of spontaneous hypoglycaemia, cortisol levels are elevated when cortisol deficiency is not the cause, whereas the levels of growth hormone during spontaneous hypoglycaemia do not correlate well with the levels of growth hormone secretory reserve measured after pharmacological provocation testing (Aynsley-Green et al, 1991). Investigation for the presence of growth hormone insufficiency therefore requires clinical assessment for other signs suggestive of inadequate growth hormone reserves (e.g. decreased height velocity, short stature and delayed bone age) combined with a provocation test (e.g. glucagon or insulin) for growth hormone secretion (Aynsley-Green et al, 1991). In the investigation of pituitary dysfunction this stimulation test is usually combined with a thyrotrophinreleasing hormone and gonadotrophin-releasing hormone provocation test, to assess complete anterior pituitary function. A lateral skull X-ray is of value to assess the size of the pituitary fossa and the presence of additional calcification suggestive of a craniopharyngioma. Treatment of panhypopituitarism is with growth hormone, cortisol and thyroxine as appropriate, with the addition of sex steroids to induce puberty at the normal age. Growth hormone therapy may need to be started in infancy to prevent hypoglycaemic episodes, before the adverse effects of growth hormone insufficiency on growth have become evident.

Cortisol insufficiency Adrenocortical insufficiency is a relatively uncommon cause of hypoglycaemia (Mackinnon and Grant, 1977; Hinde and Johnston, 1984). It results in ketotic hypoglycaemia and should therefore be considered in all patients presenting with this biochemical picture. In infancy, adrenocortical insufficiency may be secondary to congenital adrenal hyperplasia or congenital adrenal hypoplasia, whereas in older children acquired adrenal insufficiency (e.g. Addison's disease, secondary to isolated ACTH deficiency; Soltesz et al, 1985) or panhypopituitarism is a more likely cause. Rarely, the Waterhouse-Friderichsen syndrome may complicate meningococcal septicaemia. The presence of cortisol insufficiency is suggested by the presence of inappropriately low plasma cortisol levels at the time of hypoglycaemia. Further investigations should include plasma 17-hydroxyprogesterone estimations to exclude congenital adrenal hyperplasia, adrenal antibodies to exclude Addison disease and a Synacthen and either glucagon or low-dose insulin tolerance test to assess adrenal responsiveness and the integrity of the pituitary-adrenal axis, respectively. Plasma electrolytes should also be measured to exclude a concurrent salt-losing state secondary to mineralocorticoid insufficiency. Urinary steroid metabolite profiles may be of value in diagnosing errors of steroid biosynthesis.

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Treatment of cortisol insufficiency is by glucocorticoid replacement with hydrocortisone (15-25 mg/m 2 per day) in younger patients and cortisone or prednisolone in older patients. Concurrent mineralocorticoid replacement will also be necessary in salt-losing states.

Glucagon deficiency This condition is as yet unproven, though there are two case reports in the literature in which severe hypoglycaemia in infancy was found to be associated with low plasma glucagon levels (Vidnes and Oyasaeter, 1977; Kollee et al, 1978). However, from the biochemical data provided with these case reports, the possibility of abnormal insulin secretion as the aetiological factor has not been satisfactorily excluded (Aynsley-Green and Soltesz, 1985). Inborn errors of metabolism

Defects of carbohydrate metabolism Hypoglycaemia due to defects of carbohydrate metabolism include the glycogen storage diseases, disorders of hepatic gluconeogenesis, galactosaemia and hereditary fructose intolerance (Scriver et al, 1989).

Glycogen storage diseases. This group consists of conditions that are autosomal recessive enzyme defects of glycogen synthesis and/or degradation. In all cases, although fasting biochemistry, glucose and glucagon provocation tests may indicate features suggestive of one or other enzyme defect (see Cornblath and Schwartz (1991) for a more complete review), the precise diagnosis is made by demonstration of decreased enzyme activities in liver biopsies. Glycogen synthetase deficiency is a rare disease presenting with severe hypoglycaemia after short-term fasting in the neonatal period. There is no hepatomegaly and hypoglycaemia is associated with hyperketonaemia and hypoalaninaemia. Feeding causes hyperglycaemia and hyperlactataemia due to inability to store dietary carbohydrate as glycogen and overloading of the glycolytic pathway. Management therefore involves the provision of frequent small meals, rich in protein (Aynsley-Green et al, 1977). Glucose-6-phosphatase deficiency (glycogen storage disease type I or von Gierke disease) also presents most commonly with severe hypoglycaemia in the neonatal period, though a less severe form may be diagnosed in early childhood with failure to thrive, poor growth and hepatomegaly, and mild variants are being recognized with increased frequency in adult life (Pears et al, 1992). Glycogenolysis is blocked and so hypoglycaemia is associated with lactic acidosis due to activation of the glycolytic pathway. Counterregulation occurs and ketosis with hyperlipidaemia is evident. Hyperuricaemia results from excess lactic acid blocking renal excretion of uric acid. Diagnosis of the subtypes of this condition by measurement of enzyme activities in liver biopsies has been made easier by the introduction of microtechniques such

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that needle biopsies of the liver, rather than large wedge biopsies, provide adequate tissue for enzyme assays (Burchell et al, 1988). Treatment requires the provision of frequent (2- to 3-hourly) high-carbohydrate meals during daytime with overnight feeding via a nasogastric tube or gastrostomy (Greene et al, 1980). Debrancher enzyme deficiency (type III glycogenosis) and hepatic phosphorylase deficiency (type VI glycogenosis) are associated with incomplete defects of glycogenolysis and normal hepatic gluconeogenesis. Patients with these enzyme deficiencies present with hepatomegaly and mild hypoglycaemia (Hers et al, 1989) associated with ketosis, often occurring at times of intercurrent illness. Diagnosis of either condition is suggested by a large increase in lactate levels after a glucose tolerance test. Patients with phosphorylase deficiency have no change in blood glucose following glucagon in either the fed or fasted state, whereas those with debrancher enzyme deficiency show an increase in blood glucose in the fed but not in the fasting state after glucagon provocation (Hug et al, 1963). Confirmation of the diagnosis necessitates demonstration of decreased enzyme levels in a hepatic biopsy. Patients with debranching enzyme deficiency require frequent carbohydrate feeds during the first years of life with a high-protein feed at bedtime, but will outgrow the tendency to hypoglycaemia when adult. Those with phosphorylase deficiency should be managed by frequent feeding with high-protein feeds (Aynsley-Green and Soltesz, 1985).

Disorders of hepatic gluconeogenesis. This group of conditions includes deficiencies of glucose-6-phosphatase (see the section on glycogen storage disorders), fructose-l,6-diphosphatase, pyruvate carboxylase (Leigh subacute necrotizing encephalomyelopathy) and phosphoenolpyruvate carboxykinase. The latter two enzyme deficiencies are relatively rare and are described in detail elsewhere (Hommes et al, 1968; Fiser et al, 1974; Atkin et al, 1979; Cornblath and Schwartz, 1991). Lactic acidosis occurs in all of these conditions, but hypoglycaemia with hepatomegaly only occurs consistently in glucose-6-phosphatase and fructose-l,6-diphosphatase deficiencies (Saudubray et al, 1989). Fructose-l,6-diphosphatase deficiency has a biochemical picture similar to that observed in glucose-6-phosphatase deficiency (Baker and Winegrad, 1970; Gitzelmann et al, 1989), though it presents clinically with hypoglycaemia that may on occasions be less severe and later in infancy. A glycaemic response can be observed after administration of glucose, galactose, maltose and lactose but not after fructose, alanine or glycerol (Pagliara et al, 1973). Diagnosis is based on the demonstration of decreased enzyme activity in liver, white blood cells or jejunal mucosa (Cornblath and Schwartz, 1991). Therapy necessitates the avoidance for most patients of fructose and sucrose and prolonged periods of fasting. Catabolic situations such as intercurrent illness should be managed in hospital with glucose given intravenously if necessary (Dixon and Leonard, 1992).

Galactosaemia. This hereditary condition is secondary to deficiency of galactose-l-phosphate uridyl transferase. The timing and severity of onset

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may vary but hypoglycaemia occurs following a galactose-containing meal (usually milk) (Segal, 1989). Other symptoms may include diarrhoea and vomiting and associated physical signs include failure to thrive, hepatomegaly, jaundice, ascites, cataracts and mental retardation. The cause of this condition may be suggested by the presence of non-glucose reducing substances and amino acids in the urine and diagnosis is confirmed by measurement of enzyme activity in red blood cells'. Treatment involves a galactose- and lactose-free diet, with which considerable improvement in physical symptoms and signs may occur.

Hereditary fructose intolerance. This disorder occurs as a result of fructose-tphosphate aldolase deficiency and presents with symptoms following the introduction of fructose or sucrose into the diet as usually occurs at weaning. Symptoms and signs are variable and include vomiting with ketosis and hypoglycaemia, diarrhoea, hepatomegaly, jaundice, failure to thrive, haemorrhages and amino aciduria. The diagnosis is suggested by the presence of fructosuria after meals and a fructose tolerance test results in hypoglycaemia (Kaufmann and Froesch, 1973; Gitzelmann et al, 1989). Enzyme activity in a liver biopsy will be reduced. Therapy requires elimination of fructose from the diet.

Defects of amino acid metabolism Disorders of amino acid metabolism such as maple syrup urine disease and methylmalonic aciduria may cause hypoglycaemia (Donnell et al, 1967) that is associated with intense ketosis. Maple syrup urine disease is due to an enzyme deficiency (branched-chain ketoacid dehydrogenase) in branchedchain amino acid metabolism and methylmalonic aciduria is caused by an enzyme defect (methylmalonyl-CoA mutase) in the intermediary metabolism of isoleucine and valine, though the precise aetiology of the associated hypoglycaemia in these conditions is unknown. These conditions present soon after birth or in infancy and diagnosis is made by demonstration of an excess in the blood or urine of biochemical precursors to the enzyme defect. The enzyme defect can be demonstrated in cultured blood cells or fibroblasts. Treatment is with a diet appropriately restricted in precursors to the enzyme defect and avoidance of catabolic states (Ogier et al, 1990).

Defects of fatty acid metabolism In recent years, a number of enzyme defects in the metabolism of fatty acids have been described. These include defects of long-chain acyl-CoA dehydrogenase, medium-chain acyl-CoA dehydrogenase, short-chain acylCoA dehydrogenase, multiple acyl-CoA dehydrogenases, carnitine acyltransferase and 3-hydroxy-3-methylglutaryl-CoA lyase and are described in detail in Chapter 6. They are often characterized by the presentation in infancy of a clinical state similar to Reye syndrome, associated with hypoglycaemia, a disproportionately low ratio of ketones to fatty acids and normal insulin levels (Pollitt, 1989). In addition to the above

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defects of fatty acid metabolism, hereditary carnitine deficiency may lead to a similar clinical picture, as carnitine is required for the transport of longchain fatty acids into the mitochondria prior to [3-oxidation. There is also a report of two children with hypoglycaemia and excess urinary excretion of t~-hydroxy fatty acid in whom the precise defect of fatty acid metabolism has not been defined (Colle et al, 1983). When the above groups of conditions are suspected, diagnostic tests include the measurement of ketones, fatty acids and insulin levels at the time of hypoglycaemia with collection of the next urine specimen for the measurement of dicarboxylic acids, hydroxyacids, carnitine esters and glycine conjugates, which are the excretory products of the abnormal metabolites of partial mitochondrial and peroxisomal [3-oxidation (Bartlett et al, 1991). Diagnosis is confirmed by the demonstration of the enzyme defect in cultured fibroblasts. These investigations are discussed in detail in Chapter 6. Treatment is directed towards frequent high-carbohydrate, lowfat meals with the avoidance of fasting and catabolic states. Dietary measures are important not only in avoiding acute episodes of hypoglycaemia but also other longer-term complications such as myopathy and cardiomyopathy, which are probably secondary to the accumulation of long-chain dicarboxylic acids (Rocchiccioli et al, 1990). Other conditions

Hypoglycaemia may also be encountered in a number of other conditions not previously referred to. Excess ethyl alcohol intake in young children, either deliberately (MacLaren et al, 1970) or accidentally (Varma and Cincotta, 1978) may be particularly dangerous, as hypoglycaemia may be induced secondary to an inhibition of gluconeogenesis due to the accumulation of NADH2 generated by the metabolism of alcohol. Treatment requires the use of intravenous glucose, which should be given prophylactically in very young children who have ingested excessive alcohol. Other drugs such as salicylate and propranolol are also known to cause hypoglycaemia (McBride et al, 1973). Hypoglycaemia is also frequently seen in chloroquine-treated children with severe falciparum malaria (White et al, 1989). Liver disorders may predispose to hypoglycaemia, probably either due to decreased glycogen reserves or to secondary to abnormalities of hepatic enzyme activities that are required for gluconeogenesis. Viral hepatitis and Reye syndrome (Glasgow, 1984) are both known to predispose to hypoglycaemia and the clinical management of both conditions includes careful observation for the onset of hypoglycaemia and treatment as appropriate with intravenous glucose. FUTURE DEVELOPMENTS

Many areas relevant to hypoglycaemia require further research. Uncertainty remains over the definition of hypoglycaemia (Koh et al, 1988a)

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and, even though short-term metabolic and neurological studies suggest that hypoglycaemia should be defined at blood glucose levels of 2.6mmol/1 or tess (Koh, 1988b), it remains to be seen whether blood sugar levels less than this are associated with adverse long-term neurodevelopmental sequelae beyond 18 months (Lucas et al, 1988) and whether the association is causal. Such studies will require randomized, case-controlled, prospective longterm follow-up. Development of the type of experimental work described in Chapter 5 and application of techniques suitable for in vivo use in human subjects (e.g. magnetic resonance spectroscopy) may provide further answers. Exciting technological developments such as magnetic resonance spectroscopy (Iles and Cohen, 1987) and sophisticated neuroimaging techniques will lead to further progress in our understanding of the causes and effects of hypoglycaemia. These advances will allow further research, ranging from in vitro work at the molecular level (e.g. studies of mitochondrial function) to in vivo investigations on individual patients. Such methods will undoubtedly be complemented by the introduction of a wide range of chemical compounds that can be labelled with stable isotopes, thus allowing detailed in vivo measurements of substrate turnover, etc. (Bier, 1987), and that are ethically acceptable for use in studies in utero and in infants and young children° Furthermore, the development of microtechniques for biochemical investigation will ease the practical aspects of investigating small children with metabolic disorders (Burchell et al, 1988). Some authors have suggested that medium-chain acyl-CoA dehydrogenase deficiency may cause 3% of cases of sudden unexpected infant death (Howat et al, 1984) and that 10% of these deaths are caused by inherited metabolic diseases (Emery et al, 1988). However, more recent work has suggested that the incidence is probably less (Holton et al, 1991; Smith, 1992). New developments in molecular genetics may be of great value in demonstrating whether such conditions are indeed the cause of sudden unexpected death and are also likely to result in a clearer understanding of the aetiology of many biochemical disorders that result in hypoglycaemia. They may also be used as a screening technique, both in the antenatal period and in infancy. Further research remains to be done in specific pathologies such as nesidioblastosis. Sensitive new histochemical techniques are required that will enable us to understand the link between the wide range of pancreatic histological appearances that give rise to the common biochemical end-point of persistent hyperinsulinaemic hypoglycaemia (Rahier et al, 1984). These developments should lead to improved understanding of the control mechanisms of glucose homeostasis in childhood. Treatment of the inborn errors of metabolism that may cause hypoglycaemia is primarily supportive. Enzyme replacement in conditions such as the glycogen storage disorders has not yet been performed successfully, though methodological advances in the field of recombinant DNA biosynthesis or targeted gene therapy may produce the exciting possibility of an alternative therapeutic approach to patients with inborn errors of metabolism.

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