Neonatal cholestasis and hypoglycemia: Possible role ofcortisol deficiency

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577

Commentary CHILDREN come into an adult world wholly dependent on their parents, and on society at large, for protection. The adult world establishes protection for adults, or at least certain ones, in accordance with current information and beliefs. Our society, when asked, will affirm that children should also have certain protections and that when necessary government should assist parents in affording protection. This assistance may be through providing information or through surveillance of products sold and of environmental hazards that have particular relevance for children. Pediatricians play an important role in gathering and purveying information to parents and, when indicated, to government. One can cite many instances when inividuals or groups of pediatricians have recognized a hazard and brought about actions that saved lives or prevented illness in children, the preceding case report is an example of such an instance. Toys are an important part of child's life. Even wellmeaning manufacturers will err from time to time in design and produce something potentially harmful to children. The existence of a national government agency,

the Consumer Protection Safety Commission, has greatly facilitated successful action several times; the paper by Kravath is a recent one. Abbreviation used CPSC: Consumer Protection Safety Commission In the present antiregulatory climate-and it must be acknowledged that there have been excesses and even absurdities in regulation-one would hope that children could continue to have a CPSC available for pediatricians and others to turn to when appropriate. Caveat emptor is not appropriate for children. Neither can one expect parents (or grandparents!) to have the broad knowledge necessary to purchase only safe toys. If the CPSC disappears without suitable replacement, children will be big losers and pediatricians will have a heavier burden, which in some instances will produce insoluble frustration. Laurence Finberg, M.D. Montefiore Hospital and Medical Center 111 E. 210th St. New York, N Y 10467

Neonatal cholestasis and hypoglycemia." Possible role of cortisol deficiency Antoine Leblanc, M.D., Michel Odi~vre, M.D.,* Michelle Hadchouel, M.D., Dominique Gendrel, M.D., Jean-Louis Chaussain, M.D., and Raphael Rappaport, M.D., Paris, France T HE ASSOCI AT I ON of liver disease and hypopituitarism in neonates has been documented in a few reports I 3 but remains unexplained. No evidence of any infectious or infiltrative systemic disease has been found, 2 and an absence of a hormone normally released from the pituitary has been hypothesized1; a role for growth hormone, which can modulate bile acid synthesis, has been proposed? From Unitk de Recherche d'Hkpatologie Infantile & Clinique de Pbdiatrie, Universitk Paris-Sud, Hbpital d'Enfants; Service de Pbdiatrie, HOpital SaintVincent-de-Paul," and UnitO d'Endocrinologie Pkdiatrique et Diab~te, Dkpartement de Pbdiatrie, Hb,oitaI des Enfants-Malades. *Reprint address: Hbpital d'Enfants, 78 rue du Gknbral Leclerc, F-94270 BicOtre, France.

0022-3476/81/100577+04500.40/0 9 1981 The C. V. Mosby Co.

We present five patients with neonatal cholestasis associated with hypoglycemia and endocrine disorders; hypopituitarism, including ACTH deficiency, was demonstrated in two and primary adrenal insufficiency in the other three, suggesting that cortisol deficiency may play a role in this association. Abbreviation used ACTH: adrenocorticotropic hormone PATIENTS The five patients, four boys and a girl, were admitted because of neonatal cholestasis. The delivery was abnormal in three of them (Patients 2, 3, and 4), who had low Apgar scores.

578

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The Journal of Pediatrics October 1981

Figure. Patient 5. Numerous giant cells are scattered throughout the lobule, without portal fibrosis. (Liver--hematoxylin eosin; x 120.)

Manifestations of liver involvement appeared within the first weeks of life; they included jaundice with pale stools, hepatomegaly, and increased blood values of bilirubin, alkaline phosphatase, and transaminase glutamic pyruvic transaminase activity. Serum bile acid concentration was increased in Patients 4 and 5. A percutaneous or surgical liver biopsy was performed in all patients except Patient 1. Histologic changes included multinucleated giant hepatocytes scattered throughout the lobule (Figure), with mononuclear cell infiltration and minimal fibrosis in the portal areas; in Patient 2, however, both changes extended throughout the lobule and there was a noticeable degree of intralobular bile stasis; some degree of steatosis and glycogen deposition was also seen in Patient 5. There was no laboratory evidence of any infectious, metabolic, or toxic factors; Patient 2, however, had a urinary infection caused by Escherichia coli at one month of age, but cholestasis persisted after the cure of this infection. Jaundice cleared during the second month of life in Patients 1 and 3, and during the fifth month in the others, while liver size and function tests progressively returned to n o r m a l , Hypoglycemia was a constant finding, leading to the diagnosis of an endocrine disorder in three patients; it was symptomatic in Patients 1, 2, 3, and 4 and was documented within the first week of life in two (Patients 1 and

3) and during the first three months in the others. The results of endocrine evaluation are summarized in the Table. Patient 2 had growth retardation, microphallus, and cryptorchidism. Patients 2 and 4 had evidence of combined ACTH and GH deficiency, as confirmed by stimulation tests; thyroxine values were just below normal and hypothalamic dysfunction was suspected because of a high and prolonged thyroid-stimulating hormone response to thyroid-releasing hormone~; tomodensitometric examination of the skull was normal. Primary adrenal insufficiency, probably secondary to adrenal hypoplasia, was diagnosed in Patients 1 and 5, who had a salt-losing 9syndrome; both had deficient cortisol and aldosterone secretion and elevated basal plasma ACTH values. Patient 3 progressively developed statural advance, macrogenitosomia, and arterial hypertension; low plasma cortisol values were associated with markedly increased blood concentration of 11-deoxycortisol (compound S) at 19 months of age, indicating 11-hydroxylase deficiency. Replacement therapy was initiated in all patients after completion of the endocrine evaluation; in addition, Patient 3 had received a one-week course of hydrocortisone in the neonatal period when hypoglycemic. Jaundice was not clearly influenced by therapy, disappearing spontaneously in Patient 2. With the exception of Patient 1, who died at 2 years, 4 months of age from a pneumococcal

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Table. Endocrine studies

Cortisol [ Age Case ] (too) 1

2 3

T, TSH PRL GH (l~g/dl) (l~U/ml) (ng/ml) (ng/ml)

1.5 27 51 19

4

3.5 10.5

5

3.5

l l-Deoxy cortisol Ozg/ml)

8 AM

(tzg/dl)

6.4 5.5

3 2

27 3

5.5

15

16

2

11

9

(20.4)w (1.6)w (7.9)3~ (16.9)w

8 AM

(pg/ml) 90

0.5 (0.6)* (> 20)% (1.1):~

ACTH

6 (0.5)t 0.7

0.5 (4)t 238

3.6 (5.6)w

0.8 (2.7)*

220

] A ldosterone

(pg/ml)

Diagnosis

14.4 (12.5)* Adrenal hypoplasia Hypopituitarism 68 1l-Hydroxylase deficiency Hypopituitarism

10

Adrenal hypoplasia

T, = Thyroxine; TSH = thyroid-stimulating hormone; PRL = prolactin; GH = growth hormone. All studies were performed before hormonal replacement therapy except ACTH measurement in Patient I. All hormones were quantified by specific double antibody radioimmunoassay except thyroxine in Patient 3, which was measured by immunoenzyme assay (the lower edge of normal value with this last method is 5.5/~g/dl). *Provocative tests (peak values) after ACTH. tProvocative tests (peak values) after metyrapone. :~Provocativetests (peak values) after arginine. w tests (peak values) after glucagon (4). meningitis, all are in good condition with hormonal therapy; the period of follow-up now ranges from one to six years. DISCUSSION The association of "neonatal hepatitis" and hypopituitarism, well documented in some reports 1-3 or briefly mentioned in others,6 -8 has been demonstrated in two of our patients. It has been postulated that absence of a trophic hormone, 1 possibly growth hormone, 3 could be responsible for the liver dysfunction. However, in one of our patients, plasma concentrations of growth hormone were normal at 31A months of age, when liver disease and hypoglycemia were still present. Data from our other three patients, in w h o m a similar hver disease is associated with primary adrenal dysfunction, support the assumption that cortisol insufficiency, either primary or secondary to A C T H deficiency, might be the main endocrine abnormality responsible for both hypoglycemia and liver dysfunction. A m o n g the 13 patients with hypopituitarism and liver disease previously reported,l-3. 6-8 12 had evidence of hypoglycemia, and cortisol deficiency was present in the nine in w h o m it was investigated. There is experimental evidence that cortisol can influence bile formation; a reduction of bile flow has been observed in the rat after adrenalectomy. 9 Conversely, hydrocortisone infusion has been shown to increase the bile acid-independent bile flow in the dog 1~and the rat?' However, pharmacologic doses o f hydrocortisone, approximately five to 50 times higher than therapeutic

doses, are necessary to induce choleresis. 11 On the other hand, only a few patients with cortisol deficiency have clinical manifestations of liver disease. F r o m a practical point of view, we conclude that the appearance of hypoglycemia in an infant with liver dysfunction (an unusual manifestation of neonatal hepatitis) should lead to investigation of adrenal function. In fact, cortisol insufficiency, primary or secondary to A C T H deficiency, should be included among the etiologic factors of neonatal cholestasis. ADDENDUM

Since this article has been submitted, another infant has been studied: he presented with repeated episodes of hypoglycemia since the first day of life and developed neonatal cholestasis. A diagnosis of primary adrenal insufficiency without salt-losing syndrome was estabfished at the age of 3 weeks (deficient cortisol secretion contrasted to elevated plasma A C T H values). We thank Drs. Deroubaix, Nocton, and Sorez for referring these patients for study.

REFERENCES

1. Herman SP, Baggenstoss AH, and Cloutier MD: Liver dysfunction and histologic abnormalities in neonatal hypopituitarism, J PEDIATR87:892, 1975. 2. Lanes R, Blanchette V, Edwin C, Zahka K, Lee PA, Pakula LC, MacIean W, and Plotnick LP: Congenital hypopituitarism and conjugated hyperbilirubinemia in two infants, Am J Dis Child 132:926, 1978.

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Brief cffnical and laboratory observations

3. Drop SL, Colle E, and Guyda H J: HyperbiIirubinemia and idiopathic hypopituitarism in the newborn period, Acta Paediatr Scand 68:277, 1979. 4. Wandeschueren-Lodeweyckx M, Wolter R, Malvaux P, Eggermont E, and Eeckels R: The glucagon stimulation test: effects on plasma growth hormone and on immunoreactive insulin, cortisol, and glucose in children, J PED1ATR 85:182, 1974. 5. Chaussain JL, Binet E, Vassal J, and Job JC: Exploration de l'axe hypothalamo-hypophyso-thyroidien chez l'enfant, Arch Fr P6diatr 31:575, 1974. 6. Johnson JD, Hansen RC, Albritton WL, Werthemann U, and Christiansen RO: Hypoplasia of the anterior pituitary and neonatal hypoglycemia, J PEDIATR 82:634, 1973.

The Journal of Pediatrics October 1981

7.

8.

9.

10.

11.

Krause-Brucker W, and Gardner DW: Optic nerve hypoplasia associated with absent septum pellucidum and hypopituitarism, Am J Ophthalmol 89:113, 1980. Patel H, Tze W J, Crichton JU, McCormick AQ, Robinson GC, and Dolman CL: Optic nerve hypoplasia with hypopituitarism, Am J Dis Child 129:175, 1975. Bauman JW, Chang BS, and Hall FR: The effects of adrenalectomy and hypophysectomy on bile flow in the rats, Acta Endocrinol 52:404, 1966. Macarol V, Morris TQ, Baker KJ, and Bradley SE: Hydrocortisone choleresis in the dog, J Clin Invest 49:1714, 1970. Dumont M, and Erlinger S: Influence ofhydrocortisone on bile formation in the rat, Biol Gastroenterol 6:197, 1973.

Familial cholestasis with elevated sweat electrolyte concentrations John D. Lloyd-Still, M.D.,* Chicago, Ill.

CYSTIC FIBROSIS is characterized b y the triad of chronic p u l m o n a r y disease, p a n c r e a t i c insufficiency, a n d elevated sweat electrolyte c o n c e n t r a t i o n s ? A t least nine other conditions have b e e n d o c u m e n t e d on occasion as being accompanied by elevated sweat electrolyte values. ~ In several of these disorders ( a d r e n a l insufficiency, malnutrition, nephrosis, a n d h y p o t h y r o i d i s m ) the, sweat electrolytes return to n o r m a l values with treatment. This article describes two siblings with a familial cholestatic syndrome who have developed consistently elevated sweat electrolyte concentrations over several years. T h e i r underlying disorder is n o t characteristic o f CF. CASE R E P O R T S Patient 1. This female infant weighed 3.3 kg at birth and developed jaundice at 5 weeks of age. Investigations led to surgical exploration, at which time the operative cholangiogram revealed a normal extrahepatic biliary tree, and the liver biopsy showed minimal increase in fibrous tissue, intrahepatic biliary hypoplasia, and cholestasis (Fig. I). Her course was complicated by vitamin K deficiency at 14 months and rickets at 4 years of age, at which time she was re-evaluated. Physical examination at that time revealed a chronically icteric child with a psoriasiform

From the Division of Gastroenterology, Department of Pediatrics, Northwestern University, The Children's Memorial Hospital Presented in part at the 8th International Congt:ess of Cystic Fibrosis, Toronto, Canada, May 22-25, 1980. *Reprint address: Division of Gastroenterology, The Children's Memorial Hospital, 2300 Children's Plaza, Chicago, IL 60614.

rash on her scalp and body, normal facies, severe pruritus, height and weight values well below the third percentile, swelling over the costochondral junctions, and coxa vara. There was a Grade 2 systolic murmur maximal at the apex. The liver was hard, nodular, and enlarged 9 cm below the costal margin, as was the spleen 8 cm below the costal margin. The abdominal veins were dilated; esophageal varices were demonstrated on barium swatlow. A closed fiver biopsy showed a well-established biliary cirrhosis. Abbreviations used CF: cystic fibrosis BU: Bodansky units Investigations showed hemoglobin of 7.7 gm/dl; white blood cell count, 3,000/mm3; platelets, 96,000/mm~; reticulocytes, 5%; total bilirubin, 8.1 mg/dl with 5.9 mg/dl conjugated; SGOT, 54 IU/L; albumin, 4.3 gm/dl; immunoglobulins, normal; Prothrombin time, 13 seconds with a control of 11 seconds; cholesterol, 83 mg/dl (normal, 135 to 250 mg/dl); alkaline phosphatase, 129 Bodansky units (normal, 10%); c~l-antitrypsin, 470 mg/dl (normal, 200 to 400 mg/dl); ceruloplasmin, 410 mg/dl; serum bile acids, all markedly elevated; and 25-hydroxyvitamin D, undetectable. The following laboratory tests were normal or negative: serum calcium, phosphorus, cortisol, amino acids, T,, galactose-l-phosphate uridyl transferase, and electrolytes. Tests for toxoplasmosis, syphilis, rubella, cytomegalovirus, and herpes simplex were negative, as were hepatitis B surface antigen and hepatitis B surface and core antibodies. Rickets was treated with 48,000 U vitamin D daily by mouth, 1 ~.m, calcium carbonate three times daily, and orthopedic splint-

0022-3476/81/100580+04500.40/0 9 1981 The C. V. Mosby Co.