Saudi Journal of Gastroenterology
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Year : 2012  |  Volume : 18  |  Issue : 5  |  Page : 339-341
Isolated cortisol deficiency: A rare cause of neonatal cholestasis

Department of Pediatrics, King Fahad Medical City, Riyadh, Saudi Arabia

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Date of Submission20-Apr-2012
Date of Acceptance03-Aug-2012
Date of Web Publication18-Sep-2012


For decades, congenital panhypopituitarism has been recognized to cause infantile cholestasis. However, the identity of the hormone whose deficiency causes such derangement of the liver is not clear. Here, we report four cases of isolated severe cortisol deficiency presenting with neonatal cholestasis and hypoglycemia, of whom two had familial primary glucocorticoid deficiency and the other two had isolated adrenocorticotropin deficiency. The resolution of cholestasis by hydrocortisone replacement therapy suggests a causal relationship between cortisol deficiency and the development of neonatal cholestasis. In conclusion, the presentation of a young infant with cholestasis and hypoglycemia should alert pediatricians to the possibility of cortisol deficiency and prompt investigation of adrenal function should be undertaken.

Keywords: Endocrine, familial glucocorticoid deficiency, hypoglycemia, infant, liver disease

How to cite this article:
Al-Hussaini A, Almutairi A, Mursi A, Alghofely M, Asery A. Isolated cortisol deficiency: A rare cause of neonatal cholestasis. Saudi J Gastroenterol 2012;18:339-41

How to cite this URL:
Al-Hussaini A, Almutairi A, Mursi A, Alghofely M, Asery A. Isolated cortisol deficiency: A rare cause of neonatal cholestasis. Saudi J Gastroenterol [serial online] 2012 [cited 2022 Jan 25];18:339-41. Available from:

During the neonatal and early infancy period, the liver is vulnerable to injury by different mechanisms because of the relative immaturity of the synthetic and excretory functions of bile acid and bilirubin. [1] As a result, injury to the neonatal liver by infectious, metabolic, endocrine, storage, or hypoxic/ischemic diseases results ultimately in cholestatic hepatitis. [2] Multiple hormonal deficiencies (cortisol, growth hormone, thyroxin), associated with congenital panhypopituitarism, caused around 50 cases of cholestasis in neonates and young infants, as reported in the literature. [3],[4],[5],[6],[7],[8],[9],[10],[11],[12],[13] The identity of the hormone whose deficiency causes such derangement of the liver is not clear. Some authors suggested that growth hormone deficiency is the major cause of cholestasis. [13],[14],[15],[16] Only a handful of cases have been reported about the possible role of isolated cortisol deficiency in inducing neonatal cholestasis. [3],[10],[17],[18],[19]

Here, we report four cases of severe cortisol deficiency presenting with neonatal cholestasis, of whom two had familial primary glucocorticoid deficiency and the other two had isolated adrenocorticotropin hormone (ACTH) deficiency. The resolution of cholestasis by hydrocortisone replacement therapy suggests a causal relationship between cortisol deficiency and the development of neonatal cholestasis.

   Patients Top

Four male infants with a median age of 10 weeks (range 6-12 weeks) presented at our hospital between 2007 and 2011 for investigation of prolonged neonatal jaundice [Table 1]. All were full-term babies of consanguineous parents with normal birth weights. Two were delivered normally (cases 3 and 4), and the other two were delivered by cesarean section due to fetal distress. The postnatal period was uneventful apart from jaundice that started during the first week. At admission, two (cases 1 and 2) developed recurrent tonic hypoglycemic convulsions (glucose <2.4 mmol/L) and other two were noticed to develop recurrent asymptomatic hypoglycemia documented by repeated prick tests for glucose prior to feeding. The older sibling of case 1 died at age one month because of undiagnosed liver disease and hypoglycemic convulsions. On physical examination, cases 1 and 2 had generalized hyperpigmented skin. All the infants had normal male genitalia and none had dysmorphic features. Mild hepatomegaly was observed in all the infants.
Table 1: Liver enzymes in neonates with isolated adrenal insufficiency presenting with cholestasis

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Biochemical evidence of cholestatic hepatitis was observed in all the cases [Table 1]. The level of serum bile acid (normal 0-8.1 μmol/L) was elevated in three patients (cases 2, 3, 4) and normal in patient 1. Synthetic function tests of the liver were normal in all the patients. Ultrasound of the abdomen revealed mild hepatomegaly and normal adrenal glands in all the infants. Extensive workup excluded infectious, metabolic, and structural causes of neonatal cholestasis. Urine for bile acid analysis in infants with normal serum bile acid level excluded primary bile acid synthetic disorders. Results of extensive endocrine investigations during the episodes of hypoglycemia are shown in [Table 2]. All the infants had severe cortisol deficiency with very high ACTH in patients 1 and 2 and very low ACTH in patients 3 and 4. Plasma growth hormone, thyroid function tests, rennin, aldosterone, and 17-hydroxy progesterone levels were all normal. Magnetic resonance imaging of the brain in case 3 showed a normal pituitary gland and in case 4 showed a loss of the normal hyperintense signal of the adenohypophysis. No midline brain defects could be seen in both the cases. On the basis of the above findings, cases 1 and 2 were diagnosed as familial glucocorticoid deficiency, and cases 3 and 4 were diagnosed as isolated ACTH deficiency. Hydrocortisone was commenced immediately in cases 1 and 2 at a dose of 5 mg IV every six hours for two days before shifting to an oral dose of 2.5 mg three times a day. In cases 3 and 4, hydrocortisone was initiated at 2.5 mg three times a day.
Table 2: Endocrine investigations during episodes of hypoglycemia

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Genetic analysis in case 1 revealed a homozygous mutation in the coding region of the ACTH receptor (MC2R) gene consisting of one base protein insertion in exon 1 of the gene, leading to a premature stop codon after 94 amino acids, confirming the diagnosis of type 1 familial glucocorticoid deficiency. Genetic analysis in case 2 was negative for any mutation in the MC2R gene or the melanocortin 2 receptor accessory protein (MRAP)-encoding gene. Following commencement of hydrocortisone, the hypoglycemia did not recur and hyperpigmentation of the skin reduced markedly. Cholestasis resolved within three months and liver aminotransferase enzymes normalized after 6-12 months of starting hydrocortisone.

   Discussion Top

Data from our case series strongly support the hypothesis of other researchers [2],[9],[16],[17],[18] that cortisol deficiency might have a major role in the pathogenesis of cholestasis in young infants. The pathophysiologic mechanism, however, remains ill defined. In animal models, cortisol has been shown to influence bile formation. Bile flow was reduced in adrenalectomized rats, [20] and hydrocortisone infusion has been observed to enhance bile flow in a dog and rat. [21],[22] Bile acids are the major determinant and driving force for bile flow in biliary canaliculi and any alteration in bile acid synthesis or secretion leads to reduced bile flow and cholestasis. [23] Three of our patients had very high serum bile acid level which suggests that cortisol deficiency might have altered the hepatic transport of bile acids across bile canalculus, thereby diminishing bile acid concentration in bile and promoting accumulation of bile acids in hepatocytes and blood. The level of serum bile acid was normal in case 1 and mass spectroscopy analysis of urine showed no abnormal metabolites indicative of bile acid synthesis defect which suggests that cortisol deficiency might also cause cholestasis through a mechanism other than alteration of transport or synthesis of bile acids.

It is noteworthy that the presentation of adrenal insufficiency with cholestasis is limited only to the early infantile period; hepatic manifestations beyond infancy include hypertransaminasemia [24] but not cholestasis. This observation could be attributed to the relative immaturity of the synthetic and excretory functions of bile acid and bilirubin during early infancy. [1] During the study period, around 350 infants presented at our unit with cholestasis due to various etiologies; four of which (1%) was due to isolated cortisol deficiency. The presentation with hypoglycemia with or without convulsion, in addition to cholestasis was constant in all four cases and characteristic of the cases of isolated cortisol deficiency reported in the literature. [3],[10],[17],[18],[19] The pattern of liver enzymes and biochemical indices of cholestasis were not specific to isolated cortisol deficiency and could occur with other causes of cholestasis. Previous reports of isolated cortisol deficiency-associated cholestasis in young infants showed that gamma-glutamyl transferase was elevated. [10],[7] In contrast, data from our study showed that isolated cortisol deficiency could cause normal gamma-glutamyl transferase cholestasis, similar to progressive familial intrahepatic cholestasis type 1 and 2 and primary bile acid synthetic defects. [2] None of our patients had liver biopsy; however, data from the literature indicate that hepatic histological changes were not specific and showed giant cell transformation, canalicular bile stasis, Kupffer cell hyperplasia, and mononuclear cell infiltration and minimal fibrosis in portal tracts. [3],[17] Therefore, given the availability of noninvasive hormonal tests and in the right clinical setting of cholestasis and hypoglycemia, liver biopsy is not necessary for the diagnosis of suspected cortisol deficiency in young infants.

Although isolated cortisol deficiency is a treatable cause of neonatal cholestasis when diagnosed early, if left untreated, it may be fatal or lead to liver failure [18] or neurodevelopemntal disability as a result of severe recurrent hypoglycemia. Late diagnosis and initiation of hydrocortisone leads to liver cirrhosis and the need for liver transplantation during early childhood. [9]

In conclusion, the presentation of a young infant with cholestasis and hypoglycemia should alert pediatricians to the possibility of cortisol deficiency and prompt investigation of adrenal function. Isolated cortisol deficiency should be considered among the differential diagnosis of normal gamma-glutamyl transferase cholestasis in neonates and young infants.

   References Top

1.Balistreri WF, Heubi JE, Suchy FJ. Immaturity of the enterohepatic circulation in early life: Factors predisposing to "physiologic" maldigestion and cholestasis. J Pediatr Gastroenterol Nutr 1983;2:346-54.  Back to cited text no. 1
2.Balistreri WF, Bezerra JA. Whatever happened to "neonatal hepatitis"? Clin Liver Dis 2006;10:27-53, v.  Back to cited text no. 2
3.Leblanc A, Odièvre M, Hadchouel M, Gendrel D, Chaussain JL, Rappaport R. Neonatal cholestasis and hypoglycemia: Possible role of cortisol deficiency. J Pediatr 1981;99:577-80.  Back to cited text no. 3
4.Kaufman FR, Costin G, Thomas DW, Sinatra FR, Roe TF, Neustein HB. Neonatal cholestasis and hypopituitarism. Arch Dis Child 1984;59:787-9.  Back to cited text no. 4
5.Krähe J, Hauffa BP, Wollmann HA, Käser H. Transient elevation of urinary catecholamine excretion and cholestatic liver disease in a neonate with hypopituitarism. J Pediatr Gastroenterol Nutr 1992;14:153-9.  Back to cited text no. 5
6.Sheehan AG, Martin SR, Stephure D, Scott RB. Neonatal cholestasis, hypoglycemia, and congenital hypopituitarism. J Pediatr Gastroenterol Nutr 1992;14:426-30.  Back to cited text no. 6
7.Ellaway CJ, Silinik M, Cowell CT, Gaskin KJ, Kamath KR, Dorney S, et al. Cholestatic jaundice and congenital hypopituitarism. J Paediatr Child Health 1995;31:51-3.  Back to cited text no. 7
8.Choo-Kang LR, Sun CC, Counts DR. Cholestasis and hypoglycemia: Manifestations of congenital anterior hypopituitarism. J Clin Endocrinol Metab 1996;81:2786-9.  Back to cited text no. 8
9.Spray CH, Mckiernan P, Waldron KE, Shaw N, Kirk J, Kelly DA. Investigation and outcome of neonatal hepatitis in infants with hypopituitarism. Acta Paediatr 2000;89:951-4.  Back to cited text no. 9
10.Gönç EN, Kandemir N, Andiran N, Ozön A, Yordam N. Cholestatic hepatitis as a result of severe cortisol deficiency in early infancy: Report of two cases and review of literature. Turk J Pediatr 2006;48:376-9.  Back to cited text no. 10
11.Karnsakul W, Sawathiparnich P, Nimkarn S, Likitmaskul S, Santiprabhob J, Aanpreung P. Anterior pituitary hormone effects on hepatic functions in infants with congenital hypopituitarism. Ann Hepatol 2007;6:97-103.  Back to cited text no. 11
12.Binder G, Martin DD, Kanther I, Schwarze CP, Ranke MB. The course of neonatal cholestasis in congenital combined pituitary hormone deficiency. J Pediatr Endocrinol Metab 2007;20:695-702.  Back to cited text no. 12
13.DeSalvo D, Pohl JF, Wilson DP, Bryant W, Easley D, Greene J, et al. Cholestasis secondary to panhypopituitarism in an infant. J Natl Med Assoc 2008;100:342-4.  Back to cited text no. 13
14.Copeland KC, Franks RC, Ramamurthy R. Neonatal hyperbilirubinemia and hypoglycemia in congenital hypopituitarism. Clin Pediatr (Phila) 1981;20:523-6.  Back to cited text no. 14
15.Drop SL, Colle E, Guyda HJ. Hyperbilirubinaemia and idiopathic hypopituitarism in the newborn period. Acta Paediatr Scand 1979;68:277-80.  Back to cited text no. 15
16.Esberg BH, Jacobsen BB. [Isolated congenital growth hormone deficiency. Severe hypoglycemia and neonatal giant cell hepatitis]. Ugeskr Laeger 1996;158:6467-9.  Back to cited text no. 16
17.Berberoðlu M, Yiðit S, Ocal G, Kansu A, Tarcan A, Girgin N, et al . Isolated deficiency of glucocorticoids presenting with cholestasis. Acta Paediatr Jpn 1998;40:378-80.  Back to cited text no. 17
18.Cheung M, Bansal S, Aw MM, Buchanan CR, Mieli-Vergani G, Dhawan A. Liver failure in a neonate with congenital adrenal hyporesponsiveness. Eur J Pediatr 2003;162:558.  Back to cited text no. 18
19.Kim CJ, Woo YJ, Kim GH, Yoo HW. Familial glucocorticoid deficiency with a point mutation in the ACTH receptor: A case report. J Korean Med Sci 2009;24:979-81.  Back to cited text no. 19
20.Bauman JW Jr, Chang BS, Hall FR. The effects of adrenalectomy and hypophysectomy on bile flow in the rat. Acta Endocrinol (Copenh) 1966;52:404-8.  Back to cited text no. 20
21.Macarol V, Morris TQ, Baker KJ, Bradley SE. Hydrocortisone choleresis in the dog. J Clin Invest 1970;49:1714-23.  Back to cited text no. 21
22.Beher WT, Beher ME, Semenuk G. The effect of pituitary and thyroid hormones on bile acid metabolism in the rat. Metabolism 1966;15:181-8.  Back to cited text no. 22
23.Suchy FJ, Sippel CJ, Ananthanarayanan M. Bile acid transport across the hepatocyte canalicular membrane. FASEB J 1997;11:199-205.  Back to cited text no. 23
24.Gurakuqi GC, Stadlbauer V, Stepan V, Warnkross H, Trauner M. [Addison's disease as a rare cause of chronically elevated liver enzymes]. Z Gastroenterol 2006;44:179-83.  Back to cited text no. 24

Correspondence Address:
Abdulrahman Al-Hussaini
Department of Pediatrics, University of King Saud for Health Sciences, Division of Pediatric Gastroenterology, Hepatology and Nutrition, Children's Hospital, King Fahad Medical City, Riyadh Postal Code 11525
Saudi Arabia
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/1319-3767.101137

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