Cholestatic Syndromes of Infancy
This study aimed to provide the analysis of clinical presentation,
results of laboratory and imaging investigations as well as clinical outcome
of children with cholestasis. Infants with neonatal cholestasis referred
to Children`s Hospital from 2002 to 2007 were participated in the study
in a cross-sectional prospective study. Appropriate diagnostic criteria
and tests were employed for diagnosis the underlying etiologies of neonatal
cholestasis. One year mortality rate was determined. One hundred twenty
one infants, 75 males and 46 females, with the mean age of 58.3 ±15.3 (14-120) days were enrolled in study. Jaundice (94.2%) and hepatomegaly
(66.1%) were the most frequent symptom and signs on admission. Idiopathic
neonatal hepatitis (36.4%), extrahepatic biliary atresia (24.8%), metabolic
disease (20.7%), intrahepatic ductal paucity (10.7%), intrauterine infection
(3.3%) were the most frequent causes of neonatal cholestasis. One year
mortality was 5.8%. There is still not one effective and specific diagnostic
method in differentiating between the causes of cholestasis in the newborns
and infants. Some potentially important differences in the disease pattern,
initial presentation and long-term outcome are suggested from the present
study when compared to previous reports from other parts of the world.
The saga of Neonatal Cholestasis (NC) continues ever since John
Cooke in 1769 referred to mortality occurring in infants due to jaundice
(Yachha et al., 1996). It is defined as prolonged elevation of
serum levels of conjugated bilirubin (> 2 mg dL-1 or 20%
of the total bilirubin) beyond the first 14 days of life (Yachha et
al., 1996). NC is the most common liver problem in infants. The main
feature is impaired canalicular biliary flow resulting in accumulation
of biliary substances in blood and extrahepatic tissues. Infants usually
present with prolonged jaundice, pale stool, dark urine and hepatosplenomegaly.
Etiologies could be due to infectious, genetic, metabolic, or undefined
abnormalities. The incidence of NC in western countries is estimated to
be around 1 in 2500 live birth (McKiernan, 2002). The most common causes
of NC are Idiopathic Neonatal Hepatitis (INH) and extrahepatic biliary
atresia (EHBA). The incidence of EHBA has been estimated to be about 1:15000
(Venigalla and Gourley, 2004) occurring in approximately 1 of 8,000 (Asian
countries) to 1 of 18,000 (European countries) live births. Idiopathic
neonatal hepatitis comprised up to 30 to 40% of all neonatal cholestasis
cases in older series. However, during the past two decades, infants believed
to have idiopathic neonatal hepatitis were later found to have newly discovered
metabolic and genetic diseases (Sokol et al., 2003). The final
outcome of many of these causes is dependent on early diagnosis and timely
management, while the presenting clinical features are usually alike.
More than 80% of cases with EHBA, who undergo Kasai portoenterostomy before
60 days of age become jaundice-free, as compared to 20-35% that was operated
in longer time. In the infants with successful biliary drainage, a 15-year
survival of 87% has been shown (Mieli-Vergani et al., 1989). Subgroups
of NC other than EHBA also need early and targeted management. Timely
treatment of metabolic causes like galactosemia and tyrosinemia, choledochal
cyst and infections and early recognition of disorders like ductal paucity
and progressive familial intrahepatic cholestasis will decrease the morbidity
due to late presentation (Yachha, 2005). Nowadays, development of sophisticated
diagnostic modalities and methods makes the diagnosis possible in early
stages and the underlying cause could be easily discerned. In spite of
this, unfortunately there are limited data about the disease among Asian
infants. Etiologies could be different in this area and so this in homogeneity
may influence the plan of management approved in western countries. This
study aimed at evaluating etiologies and outcome of infants with NC in
Northwest of Iran.
MATERIALS AND METHODS
In a cross-sectional descriptive study, we evaluated 121 infants
with NC refereed to Children Hospital, Tabriz, Iran during a five-year
period from 2002 to 2007. The parents or main care provider were personally
interviewed by the author upon or soon after admission. Referral letter
from the referring clinician and other inpatient record, where appropriate,
was screened for additional information. Through physical examination
was performed in all patients on admission and during hospital stay. The
patients were followed for one year after admission and the mortality
rate was calculated. As our hospital is the main referral center of pediatric
disease in the Northwest region, this conclusion could be drawn that the
results of current study may be attributable to the population living
in this area. The present study was approved by the ethical committee
of Tabriz University of Medical Sciences (TUMS). Patients` parents or
person in-charge signed the consent for this study. NC was defined as
the onset of clinically apparent jaundice within the first 4 months of
life, with the conjugated bilirubin greater than 17 μmol L-1
(1 mg dL-1) if the total bilirubin was less than 85 μmol
L-1 (5 mg dL-1), or the conjugated portion of plasma
bilirubin more than 20% of the total bilirubin if the total bilirubin
was more than 85 μmol L-1 (Moyer et al., 2004).
Liver biopsy and histopathological study of extracted specimen was carried
out in all patients. Radiological study, abdominal ultrasonography, hepatobiliary
scintigraphy, chromatography, cholangiography, enzyme-linked immunosorbent
assay (ELISA) and other different lab studies were carried out where appropriate
to confirm the diagnosis of any probable underlying etiology of NC according
to guidelines and instructions recommended in authoritative sources (Maclin,
Data were analyzed with the SPSS statistical software package (version
15.0; SPSS Inc., Chicago). Continuous variables were expressed as mean
Standard Deviation (SD) and categorical data were shown as frequency and
RESULTS AND DISCUSSION
One hundred twenty one infants with definite neonatal cholestasis
were studied. They were 75 (62%) males and 46 (38%) females, with the
mean age of 58.3±15.3 (14-120) days at the time of admission. The
mean birth weight of the patients was 2824.5±587.6 (1975-3950)
g. The mean levels of serum total and direct bilirubin on admission were
9.3±3.8 and 6.2±1.5 mg dL-1, respectively. The
signs and symptoms on admission and their rates are shown in Table
1. Based on the final diagnosis, extrahepatic and intrahepatic underlying
causes were identified in 32 (26.4%) and 89 (73.6%) cases, respectively
(Table 2). After a one year follow-up, 7 (5.8%) patients
expired due to the disease. Extrahepatic biliary atresia (5 cases), idiopathic
neonatal hepatitis (1 case) and histiocytosis X (1 case) were the underlying
etiologies of neonatal cholestasis in died patients. Parents of 4 expired
patients (all with extrahepatic biliary atresia) had not allowed their
children to be operated.
||Signs and symptoms of the patients with neonatal cholestasis
|| Causes of neonatal cholestasis
|CF: Cystic fibrosis, CMV: Cytomegalovirus, EHBA: Extrahepatic
biliary atresia, GSD: Glycogen storage disease, IDP: Intrahepatic
ductal paucity, INH: Idiopathic neonatal hepatitis (giant cell hepatitis),
ISD: Iron storage disease, PFIC: Progressive familial intrahepatic
cholestasis (Byler syndrome), TORCH: Toxoplasmosis and other infections
and rubella and cytomegalovirus and herpes simplex
|| Causes of neonatal cholestasis in different studies
|EHBA: Extrahepatic biliary atresia, IAP: Indian academy
of pediatrics, IDP: Intrahepatic ductal paucity, INH: Idiopathic neonatal
hepatitis (giant cell hepatitis)
In this prospective study, we evaluated 121 infants with Neonatal Cholestasis
(NC). Majority of patients in our study were male (m/f = 1.6). The male
predominance of infants with NC has been reported in a few other Asian
studies; with a male to female ratio ranging from 1.2 to 4.5 (Aanpreung
et al., 2005; Najafi, 2006; Yachha et al., 1996). NC, as
a general term, comprises many diverse pathological entities, each one
with its specific characteristics including gender difference. However;
it seems that there is a gender preference of the disease in Asian infants.
The mean age of infants was 58.3 days (1.9 month) when they were evaluated
by our staff for the first time. Late referral of infants with NC is considered
to be one the main problems in dealing with these patients; especially
in developing countries. In two reports (Yachha et al., 1996) the
mean referral age of Indian infants with NC was 3 to 3.9 months. The mean
age of referral in Najafi`s series (2006) carried out in capital of Iran
was 4 month. The optimal age for the Kasai portoenterostomy is up to two
months (Maclin, 2004). Our patients met this recommended age and they
are in better position comparing other studies. Distinguishing between
different underlying etiologies of NC is of great importance because the
plan of treatment could literally vary. While idiopathic neonatal hepatitis
and extrahepatic biliary atresia, two major causes of NC, the latter must
be managed operatively as soon as possible; the preferred treatment of
less common metabolic and infectious causes is medical (Najafi, 2006).
Liver biopsy, is introduced as a gold-standard method in distinguishing
between diverse etiologies of NC (Bazlul Karim and Kamal, 2005; Kelly
and Stanton, 1995; Nayak and Vasdev, 2002; Moyer et al., 2004)
hence we did a liver biopsy in all infants. In current study, idiopathic
neonatal hepatitis (36.4%), extrahepatic biliary atresia (24.8%), metabolic
disease (20.7%), intrahepatic ductal paucity (10.7%) and infection (3.3%)
were the most frequent causes of NC. As shown in Table 3,
idiopathic neonatal hepatitis and extrahepatic biliary atresia are the
most common underlying cause of NC in infants in all studies. Apparently,
the main difference regarding the prevalence of etiologies of NC is related
to infectious causes. In areas with tropical-like climate (India, Malaysia,
Bangladesh and Thailand), the role of infectious causes are more prominent.
On the other hand, inborn errors of metabolism such as alpha-1 antitrypsin
deficiency in particular, are more frequent in western countries (Lee,
2008; Mieli-Vergani et al., 1989; Mowat et al., 1976; Stormon
et al., 2001). There was not such a case in this study. Najafi
(2006) supposed that this may be attributed to lack of a routine evaluation
for detecting the phenotype of alpha-1 antitrypsin deficiency in infants
with NC. It was a retrospective study. We fully evaluated the suspected
patients regarding alpha-1 antitrypsin deficiency; however no positive
result attained. Present result as well as the reports from Asian countries
lacks a significant share of alpha-1 antitrypsin deficiency in infants
with NC. It seems that alpha-1 antitrypsin deficiency is a point of discrimination
between the Asian and non-Asian patients, possibly due to racial variation.
The one-year mortality rate in our series was 5.8%. This mortality rate
is higher than 2.8% of mortality rate in Aanpreung et al. (2005).
It should be noticed that four expired infants with extrahepatic biliary
atresia did not go under operation due to their parents` noncompliance.
So the true mortality rate (2.5%) is comparable with theirs. High mortality
rate in our study indicates a comprehensive educational program for parents
of infants with NC.
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