Keywords
cholestasis - panhypopituitarism - hemochromatosis
Introduction
Congenital hypopituitarism is a rare condition associated with possible serious complications
and long-term neurological sequelae, if not promptly recognized and treated.[1]
Neonates with congenital hypopituitarism may present with or without associated developmental
defects, such as ocular, midline, and genital abnormalities. They may also present
with nonspecific symptoms, including hypoglycemia, lethargy, apnea, hemodynamic instability,
jitteriness, seizures, poor weight gain, failure to thrive, temperature instability,
micropenis, recurrent sepsis, neonatal cholestasis, and prolonged jaundice.[1]
[2]
Hypoglycemia due to panhypopituitarism is typically detected shortly after birth,
but it may occur several weeks after the neonatal period.[3]
Herman et al first postulated that the hormonal deficiencies due to congenital panhypopituitarism
were the cause of neonatal cholestasis.[4] Although the causes are still unknown and the incidence is low, it is still crucial
to evaluate any cholestatic infant to prevent progressive hepatic disease and neurological
complications.
The cholestatic jaundice most commonly associated with neonatal hypopituitarism manifests
as conjugated hyperbilirubinemia with elevated alkaline phosphatase titers.[4]
[5] The pathogenesis of cholestasis is unclear. The cholestasis resolves after replacement
of glucocorticoids or growth hormone, suggesting a role of these hormones in biliary
excretory function.[6]
We report an infant with congenital panhypopituitarism presenting with cholestasis,
hypoglycemia, and high serum ferritin level, suggesting neonatal hemochromatosis.
Case Report
A 7-week-old female infant, born to consanguineous Palestinian parents, with uneventful
pregnancy and delivery and birth weight of 3.2 kg, presented with prolonged cholestatic
jaundice, recurrent attacks of hypoglycemia since early infancy, and inadequate weight
gain. Physical examination revealed jaundice, dark-colored skin, and hepatomegaly.
Metabolic, infectious, and hormonal workups were performed. Laboratory investigations
revealed elevated transaminase levels and surprisingly very high serum ferritin level
of 2,315 ng/mL, suggesting neonatal hemochromatosis.
Urinalysis for reducing substances was negative; vertebral X-ray and ophthalmic examination
were normal; TORCH (toxoplasmosis, rubella cytomegalovirus, herpes virus, and HIV)
evaluation was negative; serum amino acid and alpha-1 antitrypsin levels were normal.
Abdominal ultrasound revealed hepatomegaly.
Neonatal hemochromatosis was ruled out by buccal mucosa biopsy that did not show hemosiderin
deposition.
Critical sample during hypoglycemia revealed inappropriately low growth hormone (GH)
and cortisol levels (cortisol level, 0.02 µg/dL and growth hormone, 8.1 ng/mL). Growth
hormone stimulation tests with arginine and clonidine were consistent with GH deficiency.
Adrenocorticotropin (ACTH) stimulation test showed significant cortisol deficiency.
Hormonal screening revealed central hypothyroidism. Brain magnetic resonance imaging
(MRI) showed mild widening of the bifrontal cerebrospinal fluid (CSF) spaces and normal
appearance of the pituitary with bright spot in place.
The patient was started on hormone replacement therapy (HRT) as soon as the diagnosis
was made with hydrocortisone 15 mg/m2 daily. Then, L-thyroxin was added, after which the patient showed significant improvement.
Blood tests revealed decreased ferritin levels, liver function tests turned to normal
within 2 months of treatment, and weight increased significantly. Hepatomegaly resolved
and no further episodes of hypoglycemia were reported. GH was not started immediately
in spite of the fact that it has an extensive action on metabolism, including liver
and carbohydrate metabolism. As the patient improved dramatically, it was started
later (before waiting for growth failure).
Laboratory results for this patient are summarized in [Table 1] (before and after 2 months of treatment).
Table 1
Lab results before and after treatment
|
Test and normal range for age
|
Before treatment (7 wk)
|
After treatment (4 mo)
|
|
AST (15–60)
|
372 U/L
|
32 U/L
|
|
ALT (13–45)
|
110 U/L
|
12 U/L
|
|
Alkaline phosphatase (150–420)
|
680 U/L
|
359 U/L
|
|
Total bilirubin (<21)
|
20.1 mg/dL
|
0.7 mg/dL
|
|
Direct bilirubin (<3.4)
|
13.9 mg/dL
|
0.1 mg/dL
|
|
Ferritin (112–450)
|
2,315 ng/mL
|
58.42 ng/mL
|
|
TSH (0.6–63)
|
5.2 mU/L
|
3.0 mU/L
|
|
FT4 (10–26)
|
9.1 pmol/L
|
18.02 pmol/L
|
|
Prolactin (4.1–28.9)
|
178 ng/mL
|
18 ng/mL
|
|
LH (prepubertal)
|
<0.1 IU/L
|
<0.1 U/L
|
|
FSH (prepubertal)
|
<0.1 mIU/L
|
<0.1 mIU/L
|
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; FSH,
follicle-stimulating hormone; FT4, free thyroxine; LH, luteinizing hormone; TSH, thyroid-stimulating
hormone.
Discussion
Factors predisposing neonatal cholestasis include immaturity of hepatic excretory
function, inborn errors of metabolism, an inherent susceptibility to viral or toxic
insult, and a stereotypic response of the immature hepatocyte to injury. The condition
demands urgent attention to identify treatable conditions to prevent progressive hepatic
disease and neurologic complications.
Panhypopituitarism can present with many symptoms, including cholestasis as the initial
presenting symptom.[6] Common clinical presentation of GH deficiency in the newborn is hypoglycemia; GH
deficiency is also commonly associated with hypopituitarism.[7]
The link between hypopituitarism and associated cholestasis is not well understood.
However, lack of GH may affect liver function through decreased bile acid synthesis
and structural abnormalities of the bile canaliculi.[6] Cortisol deficiency can also cause neonatal cholestatic hepatitis.[8]
The association of liver dysfunction with hypopituitarism was first suggested in 1956.[9] Since then, a few reports have associated neonatal hepatitis with idiopathic hypopituitarism.[3]
[4]
[5]
[6]
[10] The mechanism of liver dysfunction and the development of cholestasis in hypopituitarism
are still the subjects of debate. Isolated thyroid hormone, thyroid stimulating hormone
(TSH), GH, ACTH, and cortisol deficiencies have been shown to cause conjugated hyperbilirubinemia
but combined deficiencies have also been described.[10]
[11]
[12]
[13]
Experiments have demonstrated that cortisol can influence bile formation. Reduced
bile flow has been observed in rats after adrenalectomy.[14]
[15] Hydrocortisone replacement therapy can resolve cholestatic jaundice in patients.[4]
Prolonged jaundice in a newborn is an indicator to test thyroxine, since TSH deficiency
can be a cause of jaundice and a possible indicator of panhypopituitarism if other
pituitary hormones are deficient as well.[1]
GH has been shown to modulate bile acid synthesis in both rats and humans.[16] Giacoia et al suggested that growth hormone was necessary for bile acid secretion
rather than synthesis.[11] Hodges et al studied the composition of micellar phase during digestion of two consecutive
meals in GH deficient and control patients before and after HRT with GH replacement.[16] They concluded that HRT with GH increased the hepatobiliary secretion of bile acids
and postulated that GH influences hepatic bile acid biosynthesis.
The fact that jaundice improves after HRT suggests that pituitary hormone deficiency
may be related to the pathogenesis of cholestasis. Sheehan et al claimed that the
deficiency of one or more hormones in patients with pituitary hypofunction could either
delay the normal maturation of hepatic active transport mechanisms or inhibit bile
acid synthesis, thereby promoting the accumulation of bile acid precursors and producing
a cholestatic effect.[15]
In our case, the improvement of cholestasis with HRT over a 5-week-period supports
the role of pituitary hormones in bile acid biosynthesis. However, the patient's high
ferritin level, which was not secondary to neonatal hemochromatosis and improved dramatically
with HRT, is unusual, and raises questions regarding its pathophysiology. To our knowledge,
this is the first description of neonatal hypopituitarism presenting with high ferritin
level suggesting neonatal hemochromatosis, and improving dramatically on HRT, indicating
an acute phase reactant condition.
In conclusion, the nonspecific features of congenital hypopituitarism require a high
index of suspicion, particularly in light of this unusual presentation, to reach a
diagnosis. Timely treatment of this condition with HRT is required to prevent serious
sequelae.
