Dentifying the etiological profile of children presented with hepatomegaly admitted to a tertiary care hospital

Hue Central Hospital
Journal of Clinical Medicine - No. 64/2020 101
Original Research
IDENTIFYING THE ETIOLOGICAL PROFILE 
OF CHILDREN PRESENTED WITH HEPATOMEGALY ADMITTED 
TO A TERTIARY CARE HOSPITAL
Nguyen Khoi Quan1, Nguyen Huu Chau Duc2,3*
DOI: 10.38103/jcmhch.2020.64.15
ABSTRACT
Objectives: To identify the pattern and etiology of diseases in children presented hepatomegaly at 
Pediatrics Department in Hue Central Hospital, Vietnam.
Material and Methods: The Present study was conducted to evaluate the possible etiology and clinical 
features of children presented with hepatomegaly. A total of 107 children, from one month to fifteen years 
of age with hepatomegaly admitted in the Pediatric Department of Hue Central Hospital, Vietnam from May 
2018 to April 2019 were included in this study.
Results: The most common causes of hepatomegaly were inflammation/infection of the liver (miscellaneous 
cause included), hematological diseases and congestion heart failure with the percentage of 50.5%; 27,1% 
and 12,1%; respectively. Among the hepatitis group, viral agents account for nearly 50.0%, of which the 
most common one was Cytomegalovirus accounting for nearly 30.0%. Distribution of causes by age group 
revealed most cases in 1 year-old or younger children was caused by inflammation (53.8%), and in the older 
than 1 year-old children were hematological disorders (47.3%) which has statistical significance (P<0.05).
Conclusions: Our research observed that the most common causes of the group of ≤ 1 year old were 
hepatitis, followed by cardiovascular disease and biliary obstruction due to congenital biliary atresia, and in 
the older than 1 year group, hematological disorders was the most common.
Keywords: hepatomegaly, etiology, hepatitis
I. INTRODUCTION
Hepatomegaly is an enlargement of the liver. 
Abnormal liver enlargement is a manifestation 
of many different causes: liver disease such as 
hepatitis, biliary obstruction, or it is a sign of 
systemic causes such as sepsis, blood disease, and 
heart disease. There are many causes that can be 
cured, but others can also lead to death, or certain 
complications if the treatment is not appropriate. On 
the other hand, the size of the liver in children also 
varies depending on the age and the development of 
the body, so it is difficult to determine the abnormal 
liver enlargement in clinical practice.
Treatment of hepatomegaly strongly depends on 
the pathological mechanisms behind, so accurate 
diagnosis is crucial. Identification of the mechanism 
behind an enlarged liver is a challenge, because the 
patients rarely present with a single symptom, but
1 Faculty of Medicine, Hue University of Medicine and Pharmacy, 
Hue University
2 Pediatrics Department, Hue University of Medicine and 
Pharmacy, Hue University
3 Pediatrics Center, Hue Central Hospital
- Received: 2/6/2020; Revised: 13/8/2020;
- Accepted: 4/9/2020 
- Corresponding author: Nguyen Huu Chau Duc 
- Email: nhcduc@huemed-univ.edu.vn; Phone: 0949902121
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102 Journal of Clinical Medicine - No. 64/2020
often contemporary associated many symptoms. The 
differences in many causes and their serious effects 
on children also require early detection and prognosis 
of the serious risk factors, in order to have an early 
and appropriate treatment to prevent complications 
and death. Currently, thanks to modern testing 
techniques, most causes of hepatomegaly have been 
discovered, and the disease has been prevented 
and treated with efficiency. Unfortunately, some 
laboratory tests are not available in many healthcare 
facilities. A simple algorithm using a few common 
parameters with easy-approach is needed in the 
facilities and also for primary medical care.
All over the world as well as in Vietnam, studies 
about the etiology of hepatomegaly is limited [1]. 
Most studies focus on one specific cause, separately 
on each different study subject [2] [3]. In order to 
contribute to the subject and improve the capacity 
of diagnosis, we conducted the research with three 
objectives: to reveal the etiology of hepatomegaly 
in children; to describe the clinical and laboratory 
characteristics of hepatomegaly children, and we 
also present a clinical-approach algorithm to apply 
into practice.
II. MATERIAL AND METHODS
A total 107 children from 1 moth to 15 years of 
age admitted with hepatomegaly into the Pediatric 
Department of Hue Central Hospital, Vietnam from 
May 2018 to April 2019 included in the study. 
Children with incomplete data were excluded from 
this study. Those children presented with pushed 
down liver due to various causes are excluded 
by measuring liver span for that particular age. 
Hepatomegaly was defined as when the liver edge 
was palpated below the right costal margin at the 
mid clavicular line for infants and older children 
and the liver span should be more than the ex ... ent. Data 
were collected from register book of the patient 
by using data entry preform, which was prepared 
by the researchers themselves. After collection 
of relevant information the data were checked, 
verified, edited manually for consistency, accuracy 
and to reduce error. Statistical analysis was done 
by statistical software SPSS for windows version 
20. P values were calculated using Pearson chi-
square test. P < 0.05 was considered as significant 
and P < 0.01 as highly significant.
III. RESULTS
Based on the data collected from 107 subjects, 
the children were divided into two age groups: 1 
month to ≤1 year old (called ≤1 year) and > 1 to 15 
years old (called >1 year) (Table 2). The proportion 
of male and female between the two age groups was 
not statistically significant. 
3.1. The etiologies of hepatomegaly in children
The causes of hepatomegaly were described 
in Table 3. Three most common causes of 
hepatomegaly was inflammation/infection of 
the liver (miscellaneous causes were included), 
hematological diseases and congestion heart failure 
with the percentage of 50.5%; 27,1% and 12,1%; 
respectively. The miscellaneous cases included 
were four cases of CMV hepatitis combined with 
congenital biliary atresia.
Table 2: Distribution of disease by age
group and sex
Male Female Total
n % n % n %
≤1 year 28 26.2 24 22.4 52 48.6
P>0.05>1 year 27 25.2 28 26.2 55 51.4
Total 55 51.4 52 48.6 107 100
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Journal of Clinical Medicine - No. 64/2020 103
 Table 3: Etiology of hepatomegaly
Etiology Number of cases (and percentage)
Inflammation and infection 50 (46.8)
Bile obstruction 5 (4.7)
Heart failure 13 (12.1)
Liver cancer 4 (3.7)
Hematological disease 29 (27.1)
Other rarely causes 2 (1.9)
Miscellaneous causes (CMV 
infection combined with 
congenital biliary atresia)
4 (3.7)
Total 107 (100)
With the group of 1 moth to ≤ 1 year old, 
the three most common cause groups were 
hepatitis, followed by cardiovascular disease 
and biliary obstruction due to congenital biliary 
atresia accounting for 53.8%, 21.2% and 15.4%, 
respectively. For the group > 1 to year, the most 
common was the hematological cause, accounting 
for 47.3%, followed by inflammation and infection 
40.0%, the remaining causes include liver cancer, 
rare biliary atrophy. The difference in the proportion 
distribution was statistically significant between 
two age groups (P<0.05) but not significant between 
two genders.
The results in table 4 were shown that among 
the causes of hepatitis, the viral agent accounts for 
nearly half of cases, of which the most common was 
CMV, followed by sepsis and neonatal infection. 
Some other rare causes such as drugs, autoimmune 
and other. However, there still 20.4% of cases were 
unknown etiology.
In 54 cases of hepatitis, with the group of ≤1 
year old (31 cases), the most common cause of 
hepatitis was CMV, accounting for 15/31 (48.4%). 
After that, it was due to urgent infection accounting 
for 7/31 (22.6%). There still a large proportion of 
unknown causes was 7/31 (22.6%). For the group > 
1 year old, the most common cause of hepatitis was 
viral 8/23 cases, of which HAV was presented in 6/8 
case. The difference in the proportion distribution 
was statistically significant (P=0.001).
Table 4: Distribution of hepatitis causes 
by age group
Hepatitis cause
Number of cases
≤1 year old >1 year old
CMV 15 1
HAV 1 6
HBV 0 2
Sepsis 7 4
Drug 1 1
Autoimmune hepatitis 0 3
Hemorrhagic fever 0 1
Malaria 0 1
Unidentified causes 7 4
Total 31 23
3.2. Clinical manifestations of the children 
with hepatomegaly
In table 5, the distribution of liver size by causes 
was also remarkable. The mean sub-hepatic edge 
compared to the right costal margin was 3.3 ± 1.4 
cm. Mean value in the liver cancer group was the 
largest (5.3 ± 2.6 cm) and the difference between 
causes was statistically significant (P<0.05). Most 
causes were presented with a smooth liver surface 
(94.4%), except for the group of liver cancer with all 
four cases having a rough surface. Most causes had 
a solid liver density (86.0%). Liver tenderness was 
mainly seen in the group of hepatitis, while 36/107 
(more than 30%) cases cannot be evaluated and 
the differences in tenderness were not statistically 
significant.
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104 Journal of Clinical Medicine - No. 64/2020
Table 5: The mean sub-hepatic edge compared to 
the right costal margin
Etiology Mean size of the liver
Inflammation and 
infection
3,0 ± 1,1
Bile obstruction 3,6 ± 0,5
Heart failure 2,9 ± 0,7
Hepatoblastoma 5,3 ± 2,6
Hematological disease 3,5 ± 1,9
Other causes 3,0 ± 1,4
All causes 3,3 ± 1,4
The clinical manifestations distributed by 
causes were shown in Table 6. Manifestation of 
splenomegaly, changes in the number or composition 
of leukocytes were both not statistically significant 
when distributed by group of causes. 
Table 6: The clinical manifestations distributed by causes
Inflammation 
and Infection
(n=50)
Bile 
obstruction
(n=9)
Heart 
failure
(n=13)
Hepatoblastoma
(n=4)
Hematological 
disease
(n=29)
Other 
causes
(n=2)
Total
(n=107)
n %
Fever 20 3 8 0 16 2 49 45.8
Fatigue 30 5 13 4 28 1 81 75.7
Poor 
appetite 33 6 13 4 28 2 86 80.4
Jaundice 34 9 0 0 0 0 43 40.2
White stool 7 8 0 0 0 0 15 14.0
Dark urine 34 9 0 1 1 0 45 42.1
Vomiting 16 1 4 0 4 0 25 23.4
Abdominal 
pain 19 2 2 3 9 0 35 32.7
Diarrhea 5 1 1 0 1 0 8 0.1
Shortness 
of breath 9 0 13 1 3 1 27 25.2
3.3. Laboratory tests differences according to the causes
In the children whose hepatomegaly were hematological disorders, 83.9% had an anemia condition 
attached. Assessing the severity, most causes had a mild to moderate hepatomegaly condition, while in the 
hematology group, the rate of severe anemia was 38.7%. The difference in the above rates was statistically 
significant (P<0.05). The study revealed markedly differences in laboratory test results which were shown 
in Table 7, 8, 9 and 10.
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Table 7: Different values of the blood count indexes between causes
Inflammation 
and Infection
(n=50)
Bile 
obstruction
(n=9)
Heart 
failure
(n=13)
Hepatoblastoma
(n=4)
Hematological 
disease
(n=29)
Other 
causes
(n=2)
RBC
(M/µL)
3.8 ± 0.9 3.6 ± 0.7 4.3 ± 0.9 3.3 ± 0.8 3.1 ± 0.9
3.6 ± 
0.7 P>0.05
HGB
(g/dL)
10.0 ± 2.4 10.0 ± 1.8 12.9 ± 2.3 9.4 ± 1.8 8.4 ± 2.7
7.4 ± 
3.3 P>0.05
MCV
(fL)
79.0 ± 16.2 87.2 ± 6.3 89.2 ± 6.9 86.9 ± 13.8 86.5 ± 11.1
66.8 ± 
4.2
P<0.05
MCH
(g/dL)
28.0 ± 4.7 29.9 ± 2.9 25.0 ± 2.8 26.6 ± 5.1 28.5 ± 4.3
20.1 ± 
4.9
P<0.05
Platelets
(K/µL)
338.4
 ± 150.1
312.0
 ± 147.2
371
 ± 147.3
271.4
 ± 130.2
189.6
 ± 155.3
376.2
 ± 
373.2
P<0.05
Table 8: Compared values of the liver enzyme between hepatitis versus congenital biliary atresia cause
Inflammationand Infection
(n=50)
Congenital biliary atresia
(n=9)
AST (UI/L) 407.6 ± 546.2 253.0 ± 135.4 P>0.05
ALT (UI/L) 295.4 ± 469.9 110.4 ± 41.5 P=0.001
ALP (UI/L) 301.4 ± 227.6 463.2 ± 152.3 P>0.05
GGT (UI/L) 79.8 ± 66.7 487.6 ± 487.5 P<0.05
Table 9: The De Ritis ratio (AST/ALT) in the hepatitis group
CMV
(n=16)
HAV
(n=7)
HBV
(n=2)
Sepsis
(n=11)
Drug
(n=2)
Autoimmune 
disease
(n=3)
Hemorrhagic 
fever 
and Malaria
(n=2)
Unidentified 
cause
(n=2)
Total
(n=54)
<1 3 6 2 4 1 0 1 4 22
1-2 7 0 0 6 1 1 0 5 20
>2 6 1 0 1 0 2 0 2 12
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Table 10: Bilirubin level varies by causes
Inflammation 
and Infection
(n=50)
Bile 
obstruction
(n=9)
Heart 
failure
(n=13)
Hepatoblas-
toma
(n=4)
Hematological 
disease
(n=29)
Other 
causes
(n=2)
Total
(n=107)
Normal
13 0 12 4 29 2 61
27.1% 0 92.3% 100.0% 96.8% 100.0% 57.0%
Predominant
conjugated hyper-
bilirubinemia
19 8 0 0 0 0 27
39.6% 88.9% 0 0 0 0 25.2%
Predominant
unconjugated 
hyperbilirubinemia
9 0 1 0 0 0 10
16.7% 0 7.7% 0 3.2% 0 9.3%
Mixed
9 1 0 0 0 0 9
16.7% 11.1% 0 0 0 0 8.4%
IV. CONCLUSIONS
In our study, the most common cause of 
hepatomegaly in children was inflammation and 
infection. This result was similar to the study of 
Ajay Kumar et al. [4]. The second leading cause was 
hematological diseases including acute leukemia, 
lymphoma, bone marrow dysplasia, hematopoietic 
syndrome, thalassemia, and several other causes, 
followed by heart failure in third place. Meanwhile, 
according to the study of Kumar, the second 
leading cause was congestive heart failure and 
the hematological group is accounting for a small 
percentage (6%). The difference may be due to the 
small sample size of Kumar’s study and different 
study region, while the group of hematological 
pathology was often hospitalized in central hospital. 
The results of the distribution of causes by age 
group were also remarkable. The difference between 
the age groups may be due to the inadequate 
development of the liver in children under 1 
year old, easily reacting to infections and toxins. 
Moreover, this was an age group of incomplete 
immune systems, and inadequate immunization. 
Congenital abnormalities in metabolism as well 
as structure will often manifest mainly during this 
period. As in our study, 8 of all 9 cases of congenital 
atrophy were under 1 year old. In the group of 
children older than 1 year old, the hematological 
group took the lead, with inflammation and infection 
group took the second. This could be explained due 
to the age of detection of these diseases, especially 
the lymphoma and leukemia are rarely found 
before 1 year of age in East Asia [5] [6]. Other 
mechanism cause hepatomegaly in this group may 
be due to infiltration, so it takes time to cause liver 
enlargement.
The results show that up to 50.5% of large liver 
cases due to inflammation and infection. Among 
hepatitis causes, viral agents were the most common 
(especially CMV). Infants may acquire CMV 
infection from their mothers through intrauterine 
infection (congenital infection), through contact with 
infected genital secretions during passage through 
the birth canal (perinatal infection), or postpartum 
through breastfeeding (postnatal infection) [7]. 
The most common clinical symptoms were 
nonspecific such as fatigue and poor appetite. 
However, signs of jaundice and discolored stools 
could help navigate the cause due to inflammatory 
infections or bile congestion. Other studies 
conducted in Vietnam share the similar model 
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Journal of Clinical Medicine - No. 64/2020 107
[8] [9]. Dyspnea were also valuable to suggest 
heart failure as an underlying condition. We had 
also evaluated accompanying splenomegaly, but 
differences were not significant. 
Changes in complete blood count were most 
common in the hematological group, characterized 
by a decrease in both erythrocytes and thrombocytes, 
with an inconsistent sign of leukopenia. The MCV 
alterations between the groups were remarkable. 
These signs were consistent with pathogenesis of 
liver malfunction. Due to the heterogeneousness 
of tests, this study focused on differences between 
the inflammation, infection and biliary obstruction 
group. In the hepatitis group, increasing AST and 
ALT were dominant than ALP and GGT; while 
in the bile obstructive condition, in contrast, 
ALP and GGT were markedly increased. This 
difference was explained based on the origin of 
these enzymes. AST, ALT in hepatitis children 
reflects the destruction of hepatocytes. ALT mainly 
originated from cytoplasm while AST was highly 
localized in the mitochondria (80%) and a little in 
cytoplasm (20%) therefore increasing AST suggests 
deep and progressive damage. Beside, ALP was 
synthesized by hepatocytes and bile duct epithelial 
cells and GGT was found with high concentrations 
in the cylindrical epithelial cells of the bile duct, 
it reveals that ALP and GGT were very sensitive 
tests to detect biliary obstruction. Bilirubin level 
was normal in most causes. Bilirubin increase was 
seen in all cases with biliary obstruction and also 
in a large number of hepatitis. The obstructive 
group had direct bilirubin dominance, while in the 
hepatitis group the difference between the causes 
was not really clear.
Our research strengthens the current 
understanding of the etiology, clinical and 
laboratory manifestations of hepatomegaly. Based 
on these insights, we also propose two schemes for 
approaching the diagnosis of hepatomegaly by two 
age groups below (algorithm 1, 2).
Conflict of interests
All the authors have no conflict of interests to 
declare.
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