EDITOR'S COLUMN

Management of hyperinsulinism in infants

The article by Horev et al. 1 raises at least three important questions for further discussion: (1) Does hyperinsulinism occurring in infancy come in two "flavors," a sporadic form and a familial form? (2) What is the role of surgery in the treatment of hyperinsulinism? (3) Should one distinguish, as these authors have, between "symptomatic" and "asymp- tomatic" hypoglycemia?

S P O R A D I C V E R S U S F A M I L I A L

H Y P E R I N S U L I N I S M

Our group recently reviewed its large experience with in- fantile hyperinsulinism. 2 Our review indicates that the so- called familial and sporadic forms of hypoglycemia cannot be distinguished from each other on clinical or pathologic grounds. Moreover, when the cases from both groups are combined, the entire series can be shown to follow an auto- somal recessive pattern of inheritance, confirming and ex- tending the findings of Woolf et al., 3 and strongly suggest- ing that the familial and sporadic forms may be a single en- tity. This not only has implications with regard to genetic counseling of families with a first case of hyperinsulinism but also means that lessons learned from the large family reported by Horev et al) may be relevant to the entire pa- tient population. Therefore the authors' recommendation for "conservative" management to avoid pancreatic surgery in patients with "asymptomatic" hypoglycemia deserves particular scrutiny. Consideration of their conclusions raises anew the role of surgery in this disease and the ques- tion of how to define a safe (presumably "normal") plasma glucose concentration in affected infants.

R O L E OF S U R G E R Y

Hyperinsulinism occurring in infancy is a disorder char- acterized by the dysregulation of insulin secretion. In con- trast to the normal situation, in which there is a tight stim- ulus-secretion linkage with continuous feedback regulation, patients with hyperinsulinism seem unable to regulate insulin secretion in an appropriate manner. A therapeutic

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approach based on physiologic principles would be to sup- press the abnormal pattern of insulin release, particularly in the fasting state, or (in the best of future worlds) to under- stand the underlying basis for the dysregulation and to ef- fect a specific correction. Surgical intervention is not based on these physiologic grounds; what one hopes to achieve is the extirpation of sufficient insulin-secreting tissue so that the remaining (but still abnormally regulated) beta cells have a lesser impact on carbohydrate homeostasis. In con- trast to the total removal of the dysregulated thyroid gland in hyperthyroidism, for which it is a relatively straightfor- ward matter to provide a euthyroid state to the patient, the pancreatic surgeon has the difficult task of removing enough tissue to ameliorate the hypoglycemia but not so much that insulin-dependent diabetes mellitus will result.

Although surgery for hyperinsulinism can be viewed as an unphysiologic and essentially blind procedure, it is used be- cause current medical therapy (diazoxide, somatostatin) is

See related articles, pp. 717 and 721.

ineffective more than 50% of the time. Surgery is a last re- sort and is used to protect the infant from the potential brain damage caused by severe hypoglycemia. If surgery is to be deferred while "conservative" management is used, the attending physician must be assured that the plasma glucose levels are in the range at which the brain will be protected.

S Y M P T O M A T I C V E R S U S A S Y M P T O M A T I C H Y P O G L Y C E M I A

The authors of the current article maintain that it is ap- propriate to continue conservative management for a baby with hyperinsulinism if the hypoglycemia is asymptomatic, but that subtotal pancreatectomy should be considered for infants who have not only hypoglycemia but neurologic symptoms as well. Their own data are not strongly support- ive of such a position. The authors are reassured by the nor- mal IQs of the index patients in comparison with their un- affected siblings, but they also found clear differences be-

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7 $ 6 Editor's column The Journal of Pediatrics November 1991

tween the two groups, especially in the areas of short-term memory and visuomotor integration skills. It is not acci- dental that these deficits occur in areas of the brain known to be particularly vulnerable to hypoglycemic insult. 4 Patient 2 had a plasma glucose level as low as 14 mg/dl (0.8 mmol/L) without manifesting symptoms; patients 3 and 4 were equally symptom free, with plasma glucose levels of 18 and t4 mg/dl (1.0 and 0.8 mmol/L), respectively. No one will claim that plasma glucose concentrations in that range are "safe" even without symptoms. Where, then, is the logic that permits one to say that a blood glucose level of 35 or 40 mg/dl (1.9 or 2.2 retool/L) is acceptable if unaccom- panied by symptoms ? The unusual logic involved is carried to even greater lengths in the case of patient 4, who is said to be "symptom free with borderline hypoglycemia" (ital- ics ours). The threat to the brain posed by hyperinsulinism is particularly severe because levels of potential alterna- tive fuels for cerebral metabolism are either normal (lac- tate) or inappropriately low (B-hydroxybutyrate) and there- fore cannot substitute for the low glucose concentration. Although definitive proof cannot be shown, the ostensibly "asymptomatic" hypoglycemia may provide the simplest explanation for the clear (albeit subtle) signs of neuropsy- chotogic abnormalities in the conservatively managed pa- tients of Horev et al. 1 The lack of symptoms may testify more to the limited symptom repertoire available to the young infant than to the potential for significant neurologic sequelae posed by the hypoglycemia. Whatever may be the debatable merits of distinguishing symptomatic from asymptomatic hypoglycemia in other situations, it appears to serve no purpose to do so in infants with hyperinsulin- ism.

The debate about symptomatic versus asymptomatic hy- poglycemia in hyperinsulinism is, of course, a variation on the issue of what constitutes a normal plasma glucose level in neonates and early infancy. There is certainly no agree- ment: definitions of hypoglycemia range from 20 to 80 mg/dl (1.1 to 4.4 mmoi /L)) Pertinent lessons can perhaps be learned from what transpired with serum cholesterol values. Less than 25 years ago, a serum cholesterol concen- tration of up to 250 mg/dl (6.5 retool/L) was considered "normal" in most laboratories in the United States. 6 This definition was based on large population surveys, with the range of normal defined in a statistical fashion as the mean • 2 SD. Two factors led to serious questions as to the va- lidity of that approach. First, it was appreciated that "nor- mal" levels varied considerably, depending on the eating habits of the study population; this observation caused concern as to whether a physiologic variable so sensitive to environmental change can be defined by statistical

means alone. Second, the Framingham study showed that cholesterol levels can be considered as risk factors for heart disease, leading to the current view that a total cholesterol level of less than 180 mg/dl (4.65 retool/L) provides no additional risk and can therefore be considered safe (the term "normal" is rarely used in the current liter- ature).

In similar fashion, the most widely quoted definitions of "hypoglycemic" glucose levels in early infancy are derived from a statistical analysis of nursery populations (whole blood glucose level of 30 mg/dl [1.7 mmol/L] in term in- fants and 20 mg/dl [1.1 mmol/L] in small-for-gestational- age infants). 7 As with cholesterol, "normal" values can be changed merely by altering the nursery feeding routine; this raises anew the concern as to whether the statistical approach alone can be used to define such an important physiologic measurement. Unfortunately, there is likely never to be a definitive study (analogous to the Framingham study) that could demonstrate the risks associated with various levels of plasma glucose.

Two recent observations provide clues that may help de- fine the plasma glucose levels that carry the least potential risk of brain dysfunction. Normal adults subjected to low- dose insulin infusions had a catecholamine counterregula- tory response but no overt symptoms at plasma glucose concentrations of 50 to 60 mg/dl (2.8 to 3.3 retool/L).8 Of 11 normal infants, 10 had neural dysfunction (altered au- ditory and somatosensory evoked potentials) when plasma glucose levels fell to less than 48 mg/dl (2.7 retool/L); 5 of the 10 patients remained symptom free. 9 The fact that ho- meostatic and functional changes can be detected in both adults and infants when the plasma glucose level is in the range of 50 to 60 mg/dl implies that this range constitutes an important threshold. In the absence of clear-cut docu- mentation that plasma glucose concentrations below the lower limit of that range are safe, a truly conservative goal in managing patients with hyperinsulinism would be to maintain the plasma glucose concentration above the range of 50 to 60 mg/dl (2.8 to 3.3 retool/L) irrespective of the presence or absence of symptoms. If that goat cannot be achieved by medical management, surgical intervention may be required.

Lester Baker, MD Paul S. Thornton, MBBCh, MRCPI

Charles A. Stanley, MD Department of Pediatrics

University of Pennsylvania School of Medicine Division of Endocrinology

Children's Hospital of Philadelphia Philadelphia, PA 19104

Volume 119 Editor's column 7 5 7 Number 5

REFERENCES

1. Horev Z, Ipp M, Levey P, Daneman D. Familial hyperinsulin- ism: successful conservative management. J PEDIATR 1991; 119:717-20.

2. Thornton PS, Sumner AE, RucheUi ED, Spielman RS, Baker L, Stanley CA. Familial and sporadic hyperinsulinism: histo- pathology and segregation analysis support a single autosomal recessive disorder. J PEDIAT~ 1991;I19:721-4.

3. Woolf DA, Leonard JV, Trembath RC, Pembrey ME, Grant DB. Nesidioblastosis: evidence for autosomal recessive inher- itance. Arch Dis Child 1991;66:529-30.

4. Volpe JJ. Neurology of the newborn. 2nd ed. Philadelphia: WB Saunders, 1987:364-85.

5. Cornblath M, Schwartz R, Aynsley-Green A, Lloyd JK. Hy-

poglycemia in infancy: the need for a rational definition. Pe- diatrics 1990;85:834-7.

6. Barnett HL. Pediatrics. 15th ed. New York: Meredith Corp., 1972:1916.

7. Cornblath M, Schwartz R. Disorders of carbohydrate metab- olism in infancy. 2nd ed. Philadelphia: WB Saunders, 1976:155- 205.

8. Amiel SA, Simonson DC, Tamborlane WV, DeFronzo RA, Sherwin RS. Rate of glucose fall does not affect counterreg- ulatory hormone responses to hypoglycemia in normal and di- abetic humans. Diabetes 1987;36:516-22.

9. Koh HHG, Aynsley-Green A, Tarbit M, Lyre JA. Neural dysfunction during hypoglycemia. Arch Dis Child 1988; 63:1353-8.

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