153

materials for gluconeogenesis such as acetyl CoA. Liver biopsy studies indicate that these enzymatic changes occur 12-16 h into the fast.6Over the ensuing of starvation, muscle, brain become progressively

and more efficient in ketoacids utilisation for by using preventing glucose is believed to be crucial in fuel. Thus gluconeogenesis the phase when carbohydrate supply and glycogen reserves are low and peripheral tissues have not yet adapted to non-glucose sources of energy. Findings from MRS question the quantitative nature of this 2-3

days

theory.

adipose tissue,

,

aP measured the rate of hepatic in glycogenolysis their volunteers during a 68 h fast by 13C MRS, and calculated the net rate of hepatic glycogenolysis by multiplying changes in liver glycogen for a given time, with correction for a shrinking liver volume as identified by magnetic resonance imaging. They calculated the overall rate of gluconeogenesis from whole body glucose production by measuring tritiated glucose turnover at 22, 43, and 67 h of the fast during a primed continuous intravenous infusion and subtracting the MRScalculated glycogenolytic rate from this value. Liver glycogen concentration diminished during the fast at an almost linear rate for the first 22 h and then more gradually; some activity was still measurable at 64 h. The surprising observation in this study was the calculated net rate of hepatic glycogenolysis for the first 22 h of fasting, which accounted for only 36% of total glucose production (range 19-54%), while gluconeogenesis accounted for 64%. Such a finding conflicts sharply with previous calculations derived from isotopic uptake or splanchnic arteriovenous differences, which indicate a figure for glycogenolysis greater than 65% after 12-14 h of fasting.’g Why do these findings differ and does conventional physiological teaching need to be revised? The MRS findings confirm original physiological principles but suggest quantitative rather than qualitative differences in glycogenolytic and gluconeogenic rates during the initial phases of fasting. The results do not call into question the requirement for blood glucose concentrations to be maintained within a narrow range to preserve cerebral function. Nevertheless, the differences suggested by Rothman and colleagues raise questions about the body’s need to conserve a ready supply of glucose in the liver during food deprivation and the energy expenditure required to maintain gluconeogenesis even when the glycogen supply is only partly depleted. Could the differences be methodological rather than physiological? The first measurement of glucose production in the study was at 22 h, when glycogen stores are known to be depleted and the technique for measurement may have been unreliable because recycling of labelled glucose carbon can be appreciable during the early stages of a fast and would dilute the hydrogen label. The combination of these effects would lead to an overestimation of gluconeogenesis; Rothman

et

continuing dependence on invasive methods to calculate glucose production may undermine the advantages of MRS. We now need direct comparisons of MRS with the other techniques for metabolic measurement. 1. Cahil GF. Starvation in man. Clin Endocrinol Metab 1976; 5: 397-415. 2. Iles RA, Cohen RD. NMR as a metabolic tool. Bailliere’s Clin Endocrinol Metab 1987; 1: 937-66. 3. Rothman DL, Magnusson I, Katz LD, Shulman RG, Shulman GI. Quantitation of hepatic glycogenolysis and gluconeogenesis in fasting humans with 13C NMR. Science 1991; 254: 573-76. 4. Claus TH, Pilkis SJ. Hormonal control of hepatic gluconeogenesis: In: Litwack G, ed. Biochemical actions of hormones. Vol 8. New York: Academic Press, 1981. 5. Felig P. Amino acid metabolism in man. Annu Rev Biochem 1975; 44: 933-55. 6. Nilsson LH, Hultman E. Liver glycogen in man—the effect of total starvation or a carbohydrate-poor diet followed by carbohydrate refeeding. Scand J Clin Lab Invest 1973; 32: 325-30. 7. Wahren J, Felig P, Cerasi E, Luft R. Splanchnic and peripheral glucose and amino acid metabolism in diabetes mellitus. J Clin Invest 1972; 51: 1870-78. 8. Consoli A, Kennedy F, Miles J, Gerich J. Determination of Krebs cycle metabolic carbon exchange in vivo and its use to estimate the individual contributions of gluconeogenesis and glycogenolysis to overall glucose output in man. J Clin Invest 1987; 80: 1303-10.

Excess water administration and hyponatraemic convulsions in infancy Dilutional hyponatraemia in infants and children is usually encountered as a complication of a primary disorder, often as part of the syndrome of inappropriate antidiuretic hormone secretion.1 Rapid reduction in plasma sodium concentration over a few hours, to less than 125 mmol/l, leads to cerebral oedema and convulsions.22 If unrecognised and untreated, hyponatraemia may cause death from respiratory arrest and brainstem herniation.3Too rapid intravenous correction of the abnormality may result in central pontine myelinolysis.4 25 years ago, Dugan and Holliday5 recognised the connection between hyponatraemic convulsions in infancy and inappropriate administration of dilute feeds. The USA is now seeing a disturbing rise in this disorder. Sporadic case-reports of these convulsions appeared during the 1970s,6-10 but there has been a pronounced increase in this previously rare condition during the past decade. In 1987 Medanill described 19 infants diagnosed over 6 years in a single Baltimore hospital. More recently, 31 infants diagnosed at St Louis Children’s Hospital between 1981 and 1990 have been reported by Keating and colleagues,12 of whom nearly three-quarters were seen in the past 3 years. Most North American paediatricians reporting this disorder believe it to be under-recognised and

under-reported. Characteristically,

affected infants present at 3-6 months of age with an acute neurological syndrome characterised by generalised tonic-clonic seizure or apnoea. Opisthotonic posturing is common, and seizures may last for several hours. Respiratory failure developed in nearly half the affected children in the most recent series,12 although intubation and

154

ventilation was usually required for less than 12 hours. Mild hypothermia is almost invariable at presentation. Plasma sodium on admission is usually below 120 mmol/1; it is readily correctable and the neurological disturbance resolved promptly. Although the disorder carries a risk of brain damage, affected infants have so far had a good outcome; further hyponatraemic seizures in the same infant have occasionally been

observed.7,1O The disorder is

largely a feature of inappropriate feeding practices, most commonly in children from deprived inner city families. Administration of dilute formula feeds, plus up to 1 litre a day of water, seems to be the most important causal factor. In some cases, water had been given because of diarrhoea or other intercurrent infections, but the usual reason was simply that the family had run out of the formula provided to them. Keating et al12 noted that many of the affected infants were enrolled in the Special Supplemental Food Program for Women, Infants, and Children, under which maximum provision of infant formula is only one can per day per infant for the first 12 months of life. This allowance provides 2293 kj, or a little more than three 240 ml bottles per infant per day. For healthy 4-month-old infants, this represents the 50th percentile of observed intake. The disappearance of alternative sources of free formula, such as local churches, food pantries, and manufacturers representatives, together with greatly increased costs over the past decade, may have precipitated the sharp increase in water intoxication. Likewise, the summer clustering of cases may be explained by the added financial burden placed upon families by older siblings who no longer receive school lunches during the summer break. Other dietary factors are almost certainly important, especially the reduction in salt content of infant formulas.13 In urban America, hyponatraemia is now a more common complication than hypematraemia in gastroenteritis, and too little water has been replaced by too much.14 In contrast to convulsions secondary to hypematraemia, when up to 10% of infants may sustain permanent brain damage, hyponatraemic convulsions fortunately seem to be benign. What other factors contribute to the pathogenesis of hyponatraemia and convulsions in this disorder? The diuresis that promptly follows treatment suggests that inappropriate antidiuretic hormone secretion is unlikely to be importantY Although infants are normally able to excrete over 4 litres of free water a day, both glomerular filtration rate and tubular sodium reabsorption may be reduced in those who are undernourished.l5 Most important is the rate of fall of extracellular sodium concentration. A rapid fall over a few hours following an influx of water overwhelms excretory capacity and provokes intracellular movement of water into the brain, causing cerebral oedema and water intoxication. The disorder has been reported only

rarely outside

the USA;16-18 underdiagnosis may well be a factor. In the UK, families receiving state income support receive milk tokens that can be exchanged for sufficient formula to feed each infant in the family up to the age of 12 months. This policy, together with the common practice of introducing pasteurised milk, which is high in sodium, into the diet of inner city infants early in life, may explain why this form of water intoxication has not yet been recognised in the UK. How be treated? should the condition Administration of intravenous hypertonic saline (500 mmol/1) over 30-90 minutes in a dose calculated to correct the plasma sodium to 125 mmol/1 is said to be effective and safe. 12 However, central pontine myelinolysis may complicate too rapid an increase in plasma sodium, and it is also possible to overshoot and to produce hypematraemia. Administration of sodium in less concentrated solutions (100-150 mmol/1) is probably safer13 and just as effective in correcting the hyponatraemia.12 The reported increase in water intoxication has several implications. Dietary inquiry is crucial in the investigation of infants who present with unexplained hyponatraemic convulsions. Provision of adequate formula to deprived infants rather than an incomplete supplement seems to be important in prevention. Only 1 of the 85 infants so far reported has been breast fed;9 and breastfeeding seems to be protective. For infants with diarrhoea, the advice to give dilute formula or other solutions containing inadequate sodium is inappropriate. Instead, an accurately formulated glucose-electrolyte solution should be prescribed and its administration should be carefully

supervised. 1. Gruskin

AB, Baluarte HJ, Prebis JW, Polinsky MS, Morgenstem BZ, Perlman SA. Serum sodium abnormalities in children. Pediatr Clin North Am 1982; 29: 907-32. 2. Arieff AI, Guisado R. Effects on the central nervous system of hypernatremic and hyponatremic states. Kidney Int 1976; 10: 104-16. 3. Arieff AI, Fraser CL. Detrimental consequences of untreated hyponatremia in children. Kidney Int 1987; 31: 190 (abstr). 4. Kleinschmidt-DeMasters BK, Norenberg MD. Rapid correction of hyponatremia causes demyelination: relation to central pontine myelinolysis. Science 1981; 211: 1068-70. 5. Dugan S, Holliday MA. Water intoxication in two infants following the voluntary ingestion of excessive fluids. Pediatrics 1967; 39: 418-20. 6. Nickman SL, Buckler JMH, Weiner LB. Further experiences with water intoxication. Pediatrics 1968; 41: 149-51. 7. Crumpacker RW, Kriel RL. Voluntary water intoxication in normal infants. Neurology 1973; 23: 1251-55. 8. Schulman J. Infantile water intoxication at home. Pediatrics 1980; 66: 119-20. 9. David R, Demetrius E, Carlton Gartner J. Water intoxication in normal infants: role of antidiuretic hormone in pathogenesis. Pediatrics 1981; 68: 349-53. 10. Partridge JC, Payne ML, Leisgang JJ, Randolph JF, Rubinstein JH. Water intoxication secondary to feeding mismanagement. Am J Dis Child 1981; 135: 38-41. 11. Medani CR. Seizures and hypothermia due to dietary water intoxication in infants. South Med J 1987; 80: 421-25. 12. Keating JP, Schears GJ, Dodge PR. Oral water intoxication in infants. Am J Dis Child 1991; 145: 985-90. 13. Finberg L. Water intoxication: a prevalent problem in the city. Am J Dis Child 1991; 145: 981-82. 14. Finberg L. Too little water has become too much: the changing epidemiology of water balance and convulsions in infant diarrhea. Am J Dis Child 1986; 140: 524.

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15. Gordillo G, Soto AR, Metcoff J, Lopez E, Antillon LG. Renal adjustment in malnutrition. Pediatrics 1957; 20: 303-16. 16. Lin G-H, Huang F-Y, Hsu C-H, Chyou S-C, Lee Y-J, Chang K-L. Neonatal water intoxication secondary to feeding mismanagement. Chin Med J 1987; 39: 131-34. 17. Vanpruks V, Prapaitrakul K. Water intoxication and hyponatraemic convulsions in neonates. Arch Dis Child 1989; 64: 734-35. 18. Etzioni A, Benderley A, Levi Y. Water intoxication by the oral route in an infant. Arch Dis Child 1979; 54: 551-53.

Thyroid dysfunction

in utero

The ontogeny of thyroid function during fetal development has been much studied over the past two decades. In man, thyrotropin and thyrotropin releasing hormone (TRH) can be detected in the fetal pituitary and hypothalamus from about 10 weeks’ gestation, and thyroxine and thyrotropin appear in the circulation from 12 weeks. However, these data were largely obtained from elective abortions and from infants delivery prematurely and it is only recently that direct confirmation has been possible. Studies of fetal serum obtained by percutaneous umbilical-blood sampling (cordocentesis) from healthy or anaemic fetuses have confirmed that the fetal thyroid secretes thyroxine and the pituitary secretes thyrotropin from an early stage of gestation. 2,3 The rising concentrations of total and free thyroxine and of thyrotropin throughout gestation suggest that thyroxine does not suppress thyrotropin as it does postnatally; this finding may be related to the reduced production and circulating concentrations of tri-iodothyronine. In the hypothyroid fetus, although some thyroxine may pass across from the mother, persistently low thyroxine concentrations nevertheless lead to a rise in thyrotropin and to thyroid stimulation as shown by the goitre that sometimes develops in infants with defects of thyroid hormone

biosynthesis. The new technique of cordocentesis may lead to detection of thyroid disease in utero. In pregnant women with Graves’ disease or in those with a strong family history of congenital hypothyroidism, fetal thyroid dysfunction may be suspected because of tachycardia and growth retardation in a fetus with hyperthyroidism/ or because of ultrasound detection of a goitre in a fetus with either hyperthyroidism or hypothyroidism.6 Amniotic fluid thyroid hormone concentrations do not reliably predict fetal thyroid status in these circumstances. Direct determination of the thyroid status may now be possible by fetal blood sampling, but the risks of this procedure need to be taken into account.The possibility that these measurements could be used as an indication for in-utero treatment of fetal thyroid disease is exciting. Davidson and colleagues8 described a case in which it was difficult to determine whether a fetal goitre detected by ultrasound was the result of transplacental passage of propylthiouracil or maternal thyroidstimulating immunoglobulins in a mother being treated for Graves’ disease. Cordocentesis led to the diagnosis of fetal hypothyroidism, and the fetus was

successfully treated with injections of thyroxine into the amniotic fluid. Is such prenatal treatment justified if early postnatal therapy can reverse the effects of fetal hypothyroidism? After the introduction of neonatal screening for congenital hypothyroidism, preliminary studies of the outcome were very encouraging.99 However, evidence is now accumulating that not all the effects of fetal hypothyroidism are reversed by early treatment and that some neurological deficit may persist. Although the New England Collaborative studies10 indicated that IQ scores of children who received adequate treatment were no different from those of normal controls and that the severity of hypothyroidism at birth had no significant effect on outcome, these results were not found consistently in subsequent studies. For example, results from Melbourne, Norway, and the UK indicate that mean IQ in hypothyroid infants is significantly lower than in controls, and that children with low thyroxine concentrations at diagnosis have a less satisfactory outcome.l1-13 Consequently, complete prevention of neurological damage may be achieved only if thyroxine therapy is started before birth. Is such treatment likely to be feasible in the future? Clearly it would be impossible to evaluate fetal thyroid function routinely by use of cordocentesis, but in pregnancies known to be at risk because of a positive family history of dyshormonogenesis or the discovery of a fetal goitre on routine ultrasonography, prenatal diagnosis and treatment may be indicated to offset any risk of neurological impairment. thyroid. In: Kaplan SA, ed. Clinical pediatric endocrinology. Philadelphia: WB Saunders, 1990: 87-126. 2. Ballabio M, Nicolini U, Jowett T, Ruiz de Elvira MC, Ekins RP, Rodeck CH. Maturation of thyroid function in normal human fetuses. Clin 1. Fisher DA. The

Endocrinol 1989; 31: 565-71.

Thorpe-Beeston JG, Nicolaides KH, Felton CV, Butler J, McGregor AM. Maturation of the secretion of thyroid hormone and thyroid stimulating hormone in the fetus. N Engl J Med 1991; 324: 532-36. 4. Vulsma T, Gons MH, de Vijlder JJM. Maternal-fetal transfer of thyroxine in congenital hypothyroidism due to a total organification defect or thyroid agenesis. N Engl J Med 1989; 321: 13-16. 5. Wenstrom KD, Weiner CP, Williamson RA, Grant SS. Prenatal diagnosis of fetal hyperthyroidism using funipuncture. Obstet Gynecol 3.

1990; 76: 513-17. 6. Perelman AH, Johnson RL, Clemons RD, Finberg HJ, Clewell WH, Trujillo L. Intrauterine diagnosis and treatment of fetal goitrous hypothyroidism. J Clin Endocrinol Metab 1990; 71: 618-21. 7. Daffos F. Fetal blood sampling. Annu Rev Med 1989; 40: 319-29. 8. Davidson KM, Richards DS, Schatz DA, Fisher DA. Successful in utero treatment of fetal goiter and hypothyroidism. N Engl J Med 1991; 324: 543-46. 9. Editorial. Outcome of screening for congenital hypothyroidism. Lancet 1986; i: 1130-31. 10. New

England Congenital Hypothyroidism Collaborative. Neonatal hypothyroidism screening: status of patients at 6 years of age. J Pediatr

1985; 107: 915-18. 11. Rickards A, Coakley J, Francis I, Armstrong S, Medson H, Connelly J. Results at follow-up at 5 years in a group of hypothyroid Australian children detected by newborn screening. In: Delange F, Fisher DA, Glinoer D, eds. Research in congenital hypothyroidism. New York: Plenum, 1989: 341. 12. Heyerdahl S, Kase BF, Lie SO. Intellectual develpment in children with congenital hypothyroidism in relation to recommended thyroxine treatment. J Pediatr 1991; 118: 850-57. 13. Fuggle P, Tokar S, Grant DB. Intellectual ability of early treated children with congenital hypothyroidism: results from the UK National follow-up study. Hormone Res 1991; 35 (suppl): 16.

Excess water administration and hyponatraemic convulsions in infancy.

153 materials for gluconeogenesis such as acetyl CoA. Liver biopsy studies indicate that these enzymatic changes occur 12-16 h into the fast.6Over th...
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