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Fetal Hepatomegaly: Causes and
Associations
Kyle K. Jensen, MD
Karen Y. Oh, MD
Neel Patel, MD
Evan R. Narasimhan, MD
Alexei S. Ku, MD
Roya Sohaey, MD
Abbreviations: BWS = Beckwith-Wiedemann
syndrome, CMV = cytomegalovirus, MCA =
middle cerebral artery, PCR = polymerase
chain reaction, TAM = transient abnormal
myelopoiesis
RadioGraphics 2020; 40:589–604
https://doi.org/10.1148/rg.2020190114
Content Codes:
From the Department of Diagnostic Radiol-
ogy, Oregon Health & Science University, 3181
SW Sam Jackson Park Rd, L-340, Portland, OR
97239. Recipient of a Certificate of Merit award
for an education exhibit at the 2018 RSNA An-
nual Meeting. Received April 15, 2019; revision
requested June 18 and received July 14; accepted
July 30. For this journal-based SA-CME activity,
the authors, editor, and reviewers have disclosed
no relevant relationships. Address correspon-
dence to K.K.J. (e-mail: jensenky@ohsu.edu).
©
RSNA, 2020
SA-CME LEARNING OBJECTIVES
After completing this journal-based SA-CME
activity, participants will be able to:
„ Describe normal and abnormal imag-
ing findings of the fetal liver seen at US
and MRI.
Identify fetal hepatomegaly and imple-
„
ment a search pattern for secondary
findings that help narrow the differential
diagnosis.
Differentiate the various causes of fetal
„ of the fetal liver, including its size, are described. The specific causes
hepatomegaly.
See rsna.org/learning-center-rg.
589
WOMEN’S IMAGING
Fetal hepatomegaly is associated with significant fetal morbidity
and mortality. However, hepatomegaly might be overlooked when
numerous other fetal anomalies are present, or it might not be
noticed when it is an isolated entity. As the largest solid organ in
the abdomen, the liver can be seen well with US or MRI, and the
normal imaging characteristics are well described. The length of
the fetal liver, which can be used to identify hepatomegaly, can be
determined by measuring the liver from the diaphragm to the tip of
the right lobe in the sagittal plane. Fetal hepatomegaly is seen with
infection, transient abnormal myelopoiesis, liver storage and deposi-
tion diseases, some syndromes, large liver tumors, biliary atresia,
and anemia. Some of these diagnoses are treatable during the fetal
period. Attention to the associated findings and specific hepatic and
nonhepatic imaging characteristics can help facilitate more accurate
diagnoses and appropriate patient counseling.
©
RSNA, 2020 • radiographics.rsna.org
Introduction
Enlargement of the liver is an often overlooked yet significant finding
in the fetus and is highly associated with fetal morbidity and mor-
tality. Hepatomegaly can occur because of a primary or secondary
insult to the fetal liver or in association with genetic or congenital
syndromes. A dedicated search for the cause of the hepatomegaly is
crucial, because some diagnoses are treatable during the pregnancy
or require increased prenatal surveillance. The initial diagnosis of
hepatomegaly should trigger an extensive anatomic survey for addi-
tional abnormalities. In addition, some diagnoses that cause hepato-
megaly can be risk factors for future pregnancies; thus, an accurate
diagnosis during the index pregnancy can lead to additional screen-
ing or treatment in the next one. In this image-rich review of hepa-
tomegaly causes and associations, the normal imaging characteristics
of and anomalies associated with hepatomegaly, including fetal infec-
tion, aneuploidy, primary hepatic storage and deposition disorders,
syndromes, tumors, biliary atresia, and anemia, are discussed. This
review is intended to enhance imagers’ ability to diagnose hepa-
tomegaly, further identify associated findings, and use additional
clinical and laboratory information to suggest an accurate diagnosis
(Table 1).
590  March-April 2020 radiographics.rsna.org
TEACHING POINTS
„ At US, the normal fetal liver parenchyma has imaging char-
acteristics that are similar to those of pediatric and adult nor-
mal livers, with intermediate echogenicity, homogeneous
echotexture, and a smooth capsular contour. The MRI charac-
teristics of the fetal liver reflect the primary role of this organ in
fetal erythropoiesis, with increased iron content due to a high
fetal hemoglobin level, which results in low signal intensity
with T2-weighted MRI sequences, as well as increased levels
of protein, copper, and zinc, which result in high signal inten-
sity with T1-weighted MRI sequences.
„ The US features associated with congenital syphilis infection
have a predictable pattern, and hepatomegaly is a prominent
and early-manifesting feature of this disease. The sonographic
features of congenital syphilis are seen after 18–20 weeks of
gestation, when the fetus is sufficiently immunocompetent to
generate an inflammatory response.
„ Transient abnormal myelopoiesis (TAM) is a preleukemic syn-
drome that causes hepatomegaly almost exclusively in fetuses
and newborns with trisomy 21. This syndrome develops in up
to 10% of trisomy 21 cases.
„ Congenital hemochromatosis caused by gestational alloim-
mune liver disease (GALD) leads to liver failure and thus is fatal
during the perinatal period. However, it is possible to prevent
this disease in susceptible patients with use of intravenous
immunoglobulin. Typically, if GALD is identified as the cause
of fetal hydrops or death, in the subsequent pregnancy the
maternal patient is treated with intravenous immunoglobulin.
Therefore, when hydrops and an enlarged fetal liver are iden-
tified during an index pregnancy, a diagnosis of GALD should
be considered.
„ Previously, serial amniocentesis was performed to quantify
bilirubin levels as a measure of hemolysis; however, MCA
Doppler US has essentially replaced invasive procedures for
diagnosis and assessment of severe anemia.
Fetal Liver Imaging Characteristics
The fetal liver is routinely visualized on US im-
ages, most often on the axial view for abdominal
circumference measurement and on longitu-
dinal views for fetal bowel assessment. When
evaluating the fetal liver with US, the fetal liver
parenchyma, much like the adult liver, should
be homogeneous in echotexture, and the right
lobe should be larger than the left. The left lobe
extends variably leftward across the midline, and
the confluence of the umbilical vein and portal
vein is located slightly right of the midline. US
signs of hepatomegaly include the right lobe ex-
tending caudally beyond the inferior pole of the
right kidney, a convex and/or lobulated appear-
ance of the hepatic contour, and displacement
of the fluid-filled gastric fundus by an enlarged
left lobe.
An abdominal circumference that is enlarged
for the given gestational age is a secondary sign
of fetal hepatomegaly. Other secondary signs
include an enlarged hepatic vein and spleno-
megaly. Hepatomegaly is present when the fetal
liver length is longer than the 95th percentile
for the given gestational age. It is interesting
that the fetal liver grows rapidly during the third
trimester, a time when the growth rates of other
fetal parameters (eg, biparietal diameter, femur
length) decrease considerably (1).
As the use of fetal MRI is increasing, so are
MRI examinations of the fetal liver. At US,
the normal fetal liver parenchyma has imaging
characteristics that are similar to those of pedi-
atric and adult normal livers, with intermediate
echogenicity, homogeneous echotexture, and a
smooth capsular contour (Fig 1a, 1b) (2). The
MRI characteristics of the fetal liver reflect the
primary role of this organ in fetal erythropoiesis,
with increased iron content due to a high fetal
hemoglobin level, which results in low signal in-
tensity with T2-weighted MRI sequences, as well
as increased levels of protein, copper, and zinc,
which result in high signal intensity with T1-
weighted MRI sequences (Fig 1c, 1d) (3,4). The
maximal fetal liver length can be measured at US
in the coronal or sagittal plane and compared
with established normative values on reference
charts that relate liver length to gestational age,
with use of 95% confidence limits (1).
Fetal Infection
Hepatomegaly is a feature of fetal infection, with
the reason for the liver enlargement depending
on the infecting pathogen. Concomitant imaging
findings that suggest fetal infection are nonspe-
cific and include fetal growth restriction, hydrops,
echogenic bowel, splenomegaly, cardiomegaly, mi-
crocephaly (often with brain anomalies), abnormal
fetal calcifications, oligohydramnios, and placen-
tomegaly (1). The pathogens associated with fetal
infection can be remembered most easily by using
the acronym TORCH, which stands for toxoplas-
mosis, other (parvovirus, syphilis, Zika, varicella,
human immunodeficiency virus, etc), rubella, cyto-
megalovirus, and herpes simplex virus. The cause
of the liver disease may be direct hepatic infection
leading to fetal hepatitis, or fetal anemia and the
associated sequelae. The imaging features of the
pathogens that commonly affect the fetal liver—
specifically, cytomegalovirus (CMV), parvovirus,
and syphilis—are discussed in the following sec-
tions. It should be emphasized that many of these
features overlap.
Cytomegalovirus
CMV infection is the most common congeni-
tal infection; it affects 0.2%–2.2% of neonates
worldwide (5–8). Fetal infection with CMV
can occur after a primary maternal infection
in nonimmune women or owing to a second-
ary infection in women who were immune to
CMV before pregnancy. The rate of primary
RG  •  Volume 40  Number 2 Jensen et al  591

Table 1: Features of Fetal Hepatomegaly

Associated Diagnosis Findings in Addition to Hepatomegaly Key Points

CMV infection Microcephaly, anemia, arthrogryposis, Amniotic fluid PCR performed for
hydrops, growth restriction diagnosis
Syphilis Splenomegaly, placentomegaly, ascites Hepatomegaly is the first finding to
manifest at US and the last finding to
resolve with treatment
Lysosomal storage disorders Ascites, splenomegaly, hydrops; liver Cause of up to 30% of all nonimmune
contour may show in utero cirrhosis hydrops
Trisomy 21 and TAM Other anomalies associated with trisomy Look for enlarged liver in high-risk
21 may be present fetuses as a third-trimester finding;
10%–15% of fetuses develop TAM;
10%–20% of TAM cases progress to
leukemia
Biliary atresia Absent gallbladder in only one-fourth of “Starry night” fetal liver caused by peri-
cases hepatic fibrosis; high morbidity and
mortality
Tumors Other solid tumors are present if the At US, tumors may be isoechoic to liver
tumor is metastatic; tumors are most parenchyma; MRI may better reveal
often adrenal liver tumors owing to superior soft-
tissue contrast resolution
Anemia Elevated MCA peak systolic velocity Transfusion may be performed if neces-
is a prehydrops finding suggestive of sary
anemia
Note.—CMV = cytomegalovirus, MCA = middle cerebral artery, PCR = polymerase chain reaction, TAM =
transient abnormal myelopoiesis.

versus secondary infection depends on the
rate of immune individuals in the particular
geographic region. For example, in the United
States, approximately 70% of women are CMV
seroimmune. Twenty-five percent of congenital
infections are primary infections, while 75% of
these infections are due to a maternal second-
ary infection (9). In contrast, in Europe, where
there is a lower maternal seroprevalence (50%)
of CMV, half the cases of congenital CMV are
primary infections and half are secondary infec-
tions (9,10). Regardless of whether the infection
is a primary or secondary process, first-trimester
transmission of the virus, with the subsequent
prolonged exposure of the fetus to CMV, is be-
lieved to be the phenomenon most highly associ-
ated with fetal and newborn sequelae.
Because maternal screening for CMV is not
routinely performed, fetal infection is first sus-
pected owing to the features of CMV, and the di-
agnosis is confirmed at amniotic fluid polymerase
chain reaction (PCR) testing after amniocentesis
(5,7,11,12). Amniotic fluid PCR is more sensi-
tive than amniotic fluid culture analysis for this
pathogen. Maternal serum testing can be per-
formed to look for immunoglobulin G serocon-
version, but it is considered a screening test and
only amniotic fluid PCR testing is considered a
diagnostic test for CMV (5–12).
The US features of CMV infection are non-
specific (Fig 2). Cholestatic hepatitis, liver
insufficiency, and extramedullary hematopoiesis
can lead to the occurrence of hepatomegaly and
splenomegaly with CMV infection (5,7,13,14).
In addition, direct CMV infection of the liver can
cause punctate areas of echogenicity due to liver
calcifications, and focal areas of liver hypoecho-
genicity due to liver necrosis and microabscesses
(4,15). Other conditions caused by direct viral
infection include placentomegaly, oligohydram-
nios, echogenic kidneys due to renal infection,
echogenic bowel and bowel perforation due to
viral enterocolitis, cardiomegaly due to cardiomy-
opathy, and microcephaly and brain anomalies
due to brain infection. Fetal growth restriction
can result from direct placental infection, fetal
infection, or both. Hydrops is a late finding and
occurs owing to cardiac involvement and overall
organ failure (4,5,7).
Parvovirus B19
Parvovirus B19 is another common cause of
fetal infection. Approximately 65% of women of
childbearing age are immune to parvovirus B19;
however, 1%–2% of women in this population will
seroconvert during pregnancy such that they are
no longer immune to this virus. The overall risk of
vertical transmission in the seroconverted group is
592  March-April 2020 radiographics.rsna.org

Figure 1.  Normal fetal liver. (a) Axial US

image of the upper abdomen in a fetus
at 25 weeks gestation shows a normal
liver (calipers). Note the diffusely homo-
geneous echogenicity throughout the
parenchyma. A normal fetal stomach ()
and spleen (arrow) also are seen. (b) Sag-
ittal US image through the right lobe of
the liver (black arrows), with the superior
aspect on the right and the inferior aspect
on the left, best shows the length of the liver. The
measurement is made from the diaphragm to the in-
ferior liver edge. The inferior vena cava (white arrow)
extending to the right atrium confirms the longitudi-
nal right parasagittal plane. The liver length can also
be measured on the coronal view. Normative data for
liver length at various gestational ages are reported
in an article by Vintzileos et al (2). (c) Sagittal T1-
weighted MR image, with the head at the superior as-
pect, shows high signal intensity in a normal fetal liver
(arrows), compared with the signal intensity of the
other fetal soft tissue, owing to higher levels of pro-
tein, copper, and zinc in the liver. (d) Coronal oblique
T2-weighted MR image shows low signal intensity in
the normal fetal liver (arrow), as compared with the
signal intensity in the other fetal soft tissue, due to the
higher iron content in the liver, which is related to its
role in fetal erythropoiesis.

17%–33%, and when severe fetal anemia is present,
this risk can lead to nonimmune hydrops (8,16,17).
Parvovirus is a single-stranded DNA virus
that binds to its P antigen on human cells. This
antigen is expressed on erythrocytes, erythroblasts,
megakaryocytes, and endothelial cells, as well as in
fetal liver, heart, and placenta cells (18). Therefore,
parvovirus B19 primarily causes the destruction of
erythroid cells, with subsequent aplastic anemia,
which most often is short lived and can be treated
with fetal transfusion before hydrops occurs.
Hepatomegaly is not a primary feature of parvovi-
rus B19 infection, but it can be seen in association
with it owing to the primary attack of liver cell
antigens that occurs with the virus and the associa-
tion of hepatomegaly with anemia.
Congenital Syphilis
Hepatomegaly is an important hallmark finding
of congenital syphilis infection. The Centers for
Disease Control and Prevention have recorded
a steady increase in cases of congenital syphilis
since 2012, with this infection reported in 16 of
every 100 000 live births in 2016 (19,20). The
fatality rate associated with congenital syphilis is
6.5%, and the majority of related deaths (82%)
are stillbirths (20,21). It is important to note that
fetal and infant deaths caused by congenital syph-
ilis are directly related to insufficient treatment of
the patient with penicillin during pregnancy. The
treatment regimen is determined according to the
stage of disease, and the prevention of congeni-
tal syphilis is possible with screening and treat-
ment of the infected pregnant woman, her sexual
partner(s), and the newborn infant (19–24).
All pregnant women should undergo serologic
testing for syphilis at the first prenatal visit dur-
ing the first trimester. In high-risk populations,
third-trimester maternal screening and additional
testing at delivery are recommended (25).
Similar to the transmission of most con-
genital infections, the transmission of syphilis
to the fetus most often occurs via a vertical
transplacental route. In addition, the spirochete
is able to traverse the fetal membranes and
directly infect the amniotic fluid and fetus (23).
The chance of vertical transmission of syphilis
is related to the stage of maternal disease, with
the highest transmission rates seen with early
syphilis infection, especially if the maternal
patient has secondary syphilis. Transmission
rates of 59% associated with secondary syphi-
lis and 50% associated with early maternal
infection, as compared with transmission rates
of 29% associated with primary syphilis and
13% associated with late latent infection, have
RG  •  Volume 40  Number 2 Jensen et al  593

Figure 2.  Amniocentesis-confirmed CMV infection in a fetus at 23 weeks gestation, with subsequent in utero demise. (a) Coronal
US image of the fetal chest (left) and abdomen (right) through the liver shows hepatomegaly (calipers) and echogenic bowel (arrow).
(b) Sagittal US image of the chest (left) and abdomen (right) shows a single area of liver parenchymal echogenicity (arrow), which is
most likely a calcification. Perihepatic ascites () also is seen. (c) Four-chamber US view shows an enlarged heart that is probably due
to CMV infection–related cardiomyopathy, as well as pericardial effusion (arrows). (d) Axial spectral Doppler US image through the
left MCA shows that the peak systolic velocity is elevated for the gestational age of this fetus. This finding suggests fetal anemia that is
probably due to bone marrow suppression in the setting of CMV infection. (e) Coronal T2-weighted MR image of the fetus, with its
head at the superior aspect, also shows hepatomegaly (). Cerebral atrophy (arrows) and ventriculomegaly also are seen. (f, g) Fetal
demise occurred at 27 weeks gestation; postdelivery medical photographs show abdominal protuberance due to hepatomegaly and
ascites (f), skin petechia and bruising (arrows in f) due to anemia, and bilateral club feet (g). In addition to central nervous system
anomalies and fetal growth restriction, CMV infection is associated with arthrogryposis and club feet.
594  March-April 2020 radiographics.rsna.org

Figure 3.  Syphilis in a fetus at 32 weeks gestation. The fetus was being screened for fetal syphilis (maternal disease was documented).
(a) Coronal US image through the fetal abdomen, with the chest superior and the abdomen inferior, shows an enlarged fetal liver
(calipers). Hepatomegaly is the reference standard and earliest finding in fetuses with congenital syphilis. Dist = distance (for measur-
ing liver length). (b, c) Axial gray-scale (b) and color Doppler (c) US images through the liver, with the spine on the left and the liver
on the right, show an enlarged umbilical vein (calipers in b, arrow in c) with prominent flow. An enlarged umbilical vein is often seen
in association with hepatomegaly, and it may be the first clue that directs the sonographer to measure the liver. (d) Sagittal US im-
age of the anterior placenta shows placentomegaly (calipers), which is another early sign of syphilis. (e) In addition, the sagittal color
Doppler US image shows significant polyhydramnios (amniotic fluid index [AFI], 30 mL), which is considered a late finding of syphilis.
(f) Spectral Doppler US image through the MCA shows the peak systolic velocity to be elevated for the gestational age of this fetus,
consistent with anemia, a late finding of syphilis. Umb-PS = peak systolic velocity in the MCA. The constellation of fetal findings in this
patient, combined with documented syphilis infection, is diagnostic of congenital syphilis infection.

been reported (24). Once an abnormality (or
abnormalities) of the fetus, placenta, or amni-
otic fluid is suspected at US, the confirmatory
diagnosis can be made with amniocentesis,
amniotic fluid PCR testing, and amniotic fluid
culture analysis.
The US features associated with congenital
syphilis infection have a predictable pattern, and
hepatomegaly is a prominent and early-manifest-
ing feature of this disease (Fig 3) (26). The so-
nographic features of congenital syphilis are seen
after 18–20 weeks of gestation, when the fetus
is sufficiently immunocompetent to generate an
inflammatory response (27). The US features of
syphilis seen in addition to hepatomegaly include
placentomegaly, ascites, and polyhydramnios
(26–28). Hepatic and placental infections occur
early in the course of fetal transmission, and thus
the US findings of placentomegaly and hepato-
megaly are the earliest signs of congenital syphi-
lis. Approximately 80% of fetuses with congenital
syphilis—as compared with 33% of fetuses with
an elevated middle cerebral artery (MCA) peak
systolic velocity (related to fetal anemia), 27%
with placentomegaly, 12% with polyhydram-
nios, and 10% with ascites (26)—demonstrate
hepatomegaly.
The reason that hepatomegaly is a com-
mon feature of syphilis is believed to be acute
syphilitic hepatitis and, if myocarditis is pres-
ent, increased extramedullary hematopoiesis
due to anemia and heart failure (29). Rac et al
(26) found that the sonographic features of fetal
syphilis have a predictable pattern of regression
with successful treatment of the disease. They
noted that the earliest manifesting features, plac-
entomegaly and hepatomegaly, were the last to
regress in the treated fetus, whereas later-man-
ifesting features such as abnormal Doppler US
findings, ascites, and polyhydramnios regressed
early during the course of adequate treatment.
Therefore, hepatomegaly is the most common
feature to develop early and resolve last after
adequate treatment, and the presence of this
abnormality in a high-risk patient should raise
suspicion for possible congenital syphilis.
RG  •  Volume 40  Number 2 Jensen et al  595

Figure 4.  TAM in a fetus with trisomy 21 and duodenal atresia at 28 weeks gesta-
tion. (a) Coronal US image through the fetal abdomen, with the chest at the superior
aspect, shows a dilated stomach (arrowhead) and a persistently fluid-filled duodenum
(), suggesting duodenal atresia. In addition, the liver (arrows) is enlarged, extend-
ing into the pelvis. Hepatomegaly in a fetus with trisomy 21 is suggestive of TAM.
(b) Anteroposterior postnatal radiograph of the chest and abdomen shows the proxi-
mal duodenum () and stomach (arrowhead) to be persistently dilated, consistent with
suspected duodenal atresia. In addition, there is the suggestion of an enlarged liver (ar-
rows). This newborn was found to have TAM, which eventually resolved.

Trisomy 21 and TAM
Transient abnormal myelopoiesis (TAM) is a
preleukemic syndrome that causes hepatomegaly
almost exclusively in fetuses and newborns with
trisomy 21. This syndrome develops in up to 10%
of trisomy 21 cases (Fig 4). Hepatomegaly, with
or without splenomegaly, most often develops in
the fetus in the third trimester. In 80%–90% of
infants born with TAM, the syndrome will resolve
spontaneously. In 10%–20% of infants born
with TAM, it will progress to myeloid leukemia
of Down syndrome. Trisomy 21 combined with
GATA binding protein 1 gene (GATA1) muta-
tion results in abnormally increased hematopoi-
esis in the liver and spleen, and, in turn, causes
an increased number of peripheral blast cells
(30,31). Hypoechoic hepatomegaly that is due
to increased hematopoiesis, blast cell infiltration,
and liver congestion can be seen at US (32–34).
TAM is also associated with splenomegaly and
hydrops (ie, pericardial effusion, pleural effusion,
and ascites). Hepatomegaly and hydrops are as-
sociated with fetal death, and fetal TAM–related
stillbirth in up to one-third of cases has been
reported (30–34). Although the definitive diagno-
sis of TAM is based on laboratory results (>10%
blasts and GATA1 mutation), fetal hepatomegaly
can suggest the diagnosis prenatally (30,32).
Confirmation of the diagnosis of TAM in the
fetus requires percutaneous umbilical cord blood
sampling, and early intervention should be consid-
ered in fetuses with proven TAM. These interven-
tions include fetal transfusion or early delivery for
treatment of the newborn. Therefore, it is reason-
able to consider routinely measuring the fetal liver
length in fetuses with trisomy 21 to make a diagno-
sis of TAM earlier, especially in the third trimester.
Liver Storage and Deposition Diseases
Liver storage and deposition diseases such as
Niemann-Pick disease and congenital hemochro-
matosis are rare but important causes of fetal hep-
atomegaly. Congenital hemochromatosis caused
by gestational alloimmune liver disease (GALD)
leads to liver failure and thus is fatal during the
perinatal period. However, it is possible to prevent
this disease in susceptible patients with use of
intravenous immunoglobulin (35–38). Typically, if
GALD is identified as the cause of fetal hydrops or
death, in the subsequent pregnancy the maternal
patient is treated with intravenous immunoglobu-
lin. Therefore, when hydrops and an enlarged fetal
liver are identified during an index pregnancy, a
diagnosis of GALD should be considered.
Niemann-Pick type C disease is an autosomal
recessive neurovascular lipid storage disease as-
sociated with a poor prognosis. The majority of
infants with this disease die in the first year of life
owing to liver or cardiorespiratory failure (39,40).
The visceral involvement always precedes the neu-
rologic involvement. Therefore, hepatomegaly and
splenomegaly are early prominent findings of this
disorder, and if they are suspected, amniocentesis
can be performed to determine a diagnosis. Other
lysosomal storage diseases that can cause hepato-
megaly include Gaucher disease, Wolman disease,
sialic acid storage disease, and GM1 (monosialo-
tetrahexosylganglioside) gangliosidosis (41).
596  March-April 2020 radiographics.rsna.org

Figure 5.  Niemann-Pick disease in a fetus at 24 weeks gestation. (a) Axial US image
through the fetal upper abdomen, with the spine at the superior aspect, shows an en-
larged liver with a nodular surface (arrows), massive ascites (arrowhead), and placento-
megaly (). (b) Sagittal color Doppler US image of the chest (left) and abdomen (right)
shows the intrahepatic portion of the umbilical vein (thin arrow), the hepatic veins (thick
arrow), and the inferior vena cava (arrowhead) to be dilated. A dilated umbilical vein, re-
gardless of the cause, is often associated with hepatomegaly. (c, d) Coronal T2-weighted
MR image with the chest at the superior aspect (c), and axial T2-weighted MR image with
the spine at the posterior aspect, obtained 1 week later (d) show liver nodularity (arrows)
and ascites (). In Niemann-Pick disease, ascites is rarely associated with hydrops and is
mainly due to liver dysfunction.

The US and MRI features of fetal liver
involvement with storage and deposition dis-
eases such as Niemann-Pick disease tend to
comprise mainly liver fibrosis, cirrhosis, ascites,
and nonimmune hydrops (Fig 5). In addition
to hepatomegaly, the echogenic portal triads
(ie, “starry night” appearance of liver) are most
likely due to fibrous expansion of portal spaces
(35). In Niemann-Pick disease, the reticulo-
nodular appearance of the liver surface due to
fibrosis and/or cirrhosis is often well seen when
it is searched for owing to accompanying ascites
that facilitates an acoustic window onto the liver
surface in the fetus. The ascites is secondary to
liver dysfunction and anemia and can be isolated
or part of the findings of nonimmune hydrops.
It is interesting that with Niemann-Pick type C
disease, the ascites is more likely to be isolated
than part of hydrops, whereas with the other
lysosomal storage diseases, ascites in association
with hydrops is more common (41).
Regardless of the type of ascites involvement,
the diagnosis of recurrent nonimmune hydrops
should prompt testing for the described liver
storage and deposition disorders since the asso-
ciated risks of recurrence are high (39–43). Also,
the finding of fetal ascites should lead to careful
evaluation of the liver size and morphology and
not be dismissed as a feature of hydrops only or
erroneously believed to have a urinary origin.
Syndromes Causing Hepatomegaly
Beckwith-Wiedemann syndrome (BWS) is the
most common congenital overgrowth syndrome. It
is predominantly a multigenetic disorder caused by
epigenetic alterations in certain growth regulatory
genes, and it occurs in approximately one in 13 500
live births (4,44,45). BWS was first diagnosed
RG  •  Volume 40  Number 2 Jensen et al  597

Figure 6.  BWS in a fetus at 31 weeks gestation. (a) Coronal US image, with the chest at the superior aspect, shows hepatomegaly
(calipers), with a craniocaudal liver length of 8 cm. According to the nomogram data of Vintzileos et al (2), a normal liver length at 31
weeks gestation is 4 cm. (b) Axial US image through the anterior abdominal wall, with the spine on the right, shows an omphalocele that
consists mainly of bowel (thick arrow). Note the ascites () within the omphalocele sac. The thin arrow points to the membrane cover-
ing the sac. (c) Sagittal US image of an enlarged left kidney (arrowheads) shows associated nephromegaly. Both kidneys were enlarged.
(d) Sagittal US image of the fetal head shows an enlarged tongue (thick arrow) protruding from the mouth and a normal nasal bone (thin
arrow). (e) Surface-rendered three-dimensional US image of the fetal face also shows macroglossia with persistent tongue protrusion.

prenatally in 1980, and the most common prenatal
US findings (Fig 6) include macroglossia, ompha-
locele, polyhydramnios, and macrosomia due to
visceromegaly (of which hepatomegaly is a promi-
nent feature). In addition, this syndrome is associ-
ated with an increased risk of embryonal tumors,
which are rarely identified in utero (4,44,46,47).
Sonographic findings are variably present, and
this can make the diagnosis more difficult. Wil-
liams et al (48) developed criteria to describe the
major and minor features of BWS, with macro-
somia, macroglossia, and omphalocele being the
three major findings and the remaining findings
described as minor. According to the Williams et
al criteria, a diagnosis of BWS is suggested when
either two major findings or one major finding
and two minor findings are present. In their study
(48), all previously recorded antenatal diagnoses
of BWS in the literature met these criteria. How-
ever, it is important to note that the diagnosis of
macrosomia is often based on a large abdominal
circumference. Of note, the fetal liver is the main
contributing organ for the abdominal circumfer-
ence measurement, being much larger than the
fluid-filled stomach and spleen at the standard
abdominal circumference level.Therefore, hepa-
tomegaly probably has greater significance in the
diagnosis of fetal BWS than has been recognized.
Because these findings are variably identified
prenatally, a complete sonographic evaluation is
necessary for an accurate diagnosis when only
one finding is identified (49).
Mulik et al (47) described an anatomic US scan
obtained at 18 weeks gestation that showed only
increased abdominal circumference, marked hepa-
tomegaly, and pancreatomegaly, without character-
istic findings of macroglossia or polyhydramnios.
Postmortem autopsy findings confirmed the pres-
ence of these findings, and genetic analysis results
were consistent with BWS. Therefore, the identifi-
cation of hepatomegaly should trigger an extensive
anatomic survey for additional abnormalities. Al-
ternatively, other features of BWS should trigger a
search for hepatomegaly and enlargement of other
organs. Antenatal diagnosis of BWS is essential for
reducing the morbidity and mortality in cases that
are not diagnosed at delivery, most seriously the
hyperinsulinemic hypoglycemia seen in approxi-
mately 50% of BWS cases as a result of altered
pancreatic β-cell potassium channels (49,50).
598  March-April 2020 radiographics.rsna.org

Figure 7.  Jacobsen syndrome, a chro-

mosone 11q deletion disorder, in a fetus
at 34 weeks gestation. (a) Axial US im-
age through the upper abdomen, with
the spine on the left, shows a medially
displaced stomach (arrowhead) second-
ary to an enlarged spleen (arrows). These
findings led to measurement of the liver,
which also was enlarged. Hepatomegaly
is often associated with splenomegaly.
(b) Four-chamber US view of the heart
shows cardiomegaly (heart circumfer-
ence [Circ] > 50% of thoracic circumfer-
ence). Chromosone 11q deletion dis-
orders are associated with anemia due
to abnormal platelet function, which is
probably the cause of the cardiomegaly
in this case. (c) Axial US view through
the posterior neck shows a complex fluid
collection (arrows), a cystic hygroma.
This finding is highly associated with
lymphatic disorders, genetic abnormali-
ties, and syndromes. (d) Axial postnatal
CT image through the upper abdomen
shows hepatomegaly (arrows) and sple-
nomegaly (). Jacobsen syndrome, or
partial 11q monosomy syndrome, is
one of many syndromes associated with
hepatosplenomegaly, and the additional
findings raised suspicion for a genetics-
or syndrome-related diagnosis in this
fetus.

The antenatal identification of hepatomegaly identification of subtle variants such as spleno-

can also prompt further imaging and clinical eval-
uations for less common syndromes. For example,
Jacobsen syndrome is a rare syndrome caused by
monosomy of chromosome 11q, and it occurs in
approximately one in 100 000 births (51). Patients
with Jacobsen syndrome have various pheno-
typic manifestations, but they most typically have
characteristic facial, cardiovascular, and gastroin-
testinal abnormalities. When Jacobsen syndrome is
suspected, cytogenetic analysis of chorionic villous
samples or amniocentesis can be performed to
recognize this syndrome antenatally (52).
In a recent case of Jacobsen syndrome at our
institution, visualization of the medial displace-
ment of the stomach on the abdominal circum-
ference view at US led to the identification of
splenomegaly (Fig 7). Further scanning revealed
hepatomegaly, and antenatal cytogenetic evalu-
ation revealed abnormality at chromosome 11q.
Accurate sonographic evaluation of the fetus is
dependent on acquisition of standardized images
at specific locations and orientations. In the upper
abdomen, the standard anatomic transverse US
image obtained for abdominal circumference mea-
surement is used to localize the stomach on the
left in the abdomen, with the branching vascula-
ture at the midline corresponding to the umbilical
vein and right portal vein (53). Familiarity with
the conventional fetal abdominal anatomy enables
megaly, which should prompt measurement of the
liver to identify associated hepatomegaly.
Benign and Malignant
Fetal Hepatic Tumors
Liver tumors may be a rare cause of fetal liver
enlargement, and at times they can be isoechoic
to the normal liver parenchyma and have the ap-
pearance of primary hepatomegaly. Benign and
malignant liver tumors have variable appearances
at US, and both tumors tend to be hypoechoic
(Table 2). The most common malignant process
in the fetal liver is hepatoblastoma (Fig 8), which
portends worse outcomes than do other liver tu-
mors (54,55). Hepatic hemangiomas followed by
mesenchymal hamartoma are the most common
benign processes in the fetal liver (56). Hepato-
blastoma typically appears as a lobulated solid
mass with a vascular “spoke-wheel” morphol-
ogy (57). Metastatic neuroblastoma (Fig 9), the
next most common malignant lesion in the fetal
liver, has a nodular heterogeneous hyperechoic
appearance, with or without vascularity, at US
(58,59). Both hepatoblastomas and neuroblas-
tomas may contain calcifications, and both can
grow rapidly during pregnancy, placing the fetus
at risk for high-output heart failure and hydrops.
Hemangiomas can be vascular cystic hypoechoic
lesions (60). Mesenchymal hamartomas are typi-
RG  •  Volume 40  Number 2 Jensen et al  599

Table 2: Imaging Findings of Fetal Liver Tumor

Tumor Status Tumor Type Imaging Findings

Benign Focal nodular hyperplasia Hypoechoic lesion with vascularity at Doppler US
Hemangioma Hypoechoic cystic lesion with or without punctate calcifica-
tions; vascularity at Doppler US
Hemangioendothelioma Dilated intrahepatic vessels, elevated maternal serum
α-fetoprotein
Mesenchymal hamartoma Usually a large multiloculated cystic mass
Arterial venous malformations or Multiple enlarged intrahepatic vessels
fistulas
Simple cysts Anechoic, without vascularity
Intrahepatic meconium pseudocysts Related to perforation, multiple intrahepatic complex cysts
Malignant Hepatoblastoma Solid, spoke-wheel, vascular multilobular mass with or with-
out calcifications
Metastatic neuroblastoma Heterogeneous hyperechoic nodule with or without vascularity

Figure 8.  Hepatoblastoma with the appearance of hepatomegaly. (a) Coronal oblique US image through the liver, with the chest
at the superior aspect, in a fetus at 29 weeks gestation shows an enlarged liver (white arrows) with parenchymal heterogeneity (black
arrows). The diagnosis of a focal mass was not considered, and fetal MRI was not performed. (b) Axial postnatal US image of the
liver shows a large heterogeneous mass (calipers) in the right hepatic lobe. However, the mass is nearly isoechoic to the background
parenchyma (). (c) Coronal T2-weighted postnatal MR image shows the large solid cystic right hepatic lobe mass (arrows), which
has a clearly different signal intensity, as compared with the normal liver (). The findings in this case emphasize the importance of
performing fetal MRI when the liver is enlarged and heterogeneous without a discrete mass at US.

cally large multiloculated cystic masses (61,62).
Hepatic focal nodular hyperplasia in a fetus may
appear as a hypoechoic vascular mass (55). Less
commonly, hepatic hemangioendotheliomas can
manifest as dilated intrahepatic vessels with a
concurrent elevated maternal α-fetoprotein level
(63). Intrahepatic meconium pseudocysts may be
considered in the appropriate clinical context and
appear as multiple complex intrahepatic cysts
(64). Finally, simple hepatic cysts and arteriove-
nous malformations and fistulas have the ex-
pected US characteristics (65).
Biliary Atresia
Biliary atresia indicates progressive biliary ductal
destruction and fibrosis that can lead to hepa-
tomegaly and cirrhosis (Fig 10). This anomaly
occurs in approximately one in 14 000 to one in
20 000 live births. The exact cause of biliary atresia
is unclear and is probably multifactorial. However,
90% of cases are generally believed to be isolated
and 10% are syndromic, with associated poly-
splenia, situs inversus, and other abnormalities
(66–69). Biliary atresia accounts for half of neo-
natal cholestasis cases, is the most common cause
of pediatric hepatic transplants, and is fatal if left
untreated. Therefore, it is essential to diagnose this
anomaly as early as possible to guide clinical man-
agement (70–72). However, the prenatal diagnosis
of biliary atresia is challenging and almost never
definitive. Although the results of many studies
(70,71,73) have shown a correlation between non-
visualization of the gallbladder and risk of biliary
atresia, an absent gallbladder is not diagnostic of
biliary atresia. Alternatively, biliary atresia can oc-
cur in the presence of a visualized gallbladder.
600  March-April 2020 radiographics.rsna.org

Figure 9.  Metastatic neuroblastoma in a fetus at 35 weeks gestation. (a) Sagittal oblique US image through the liver, with the
chest on the right, shows an enlarged liver (black arrows), with a focal heterogeneous mass (white arrows) in the posterior right lobe
suggested. (b) Coronal oblique color Doppler US image, with the chest on the right, shows abnormal tortuous intrahepatic vessels
(arrows) in the area of heterogeneity. (c) Axial US image through the abdomen, with the spine on the right, shows bilateral retroperi-
toneal masses (arrows) separate from the liver mass and superior to the kidneys. (d) Coronal T2-weighted MR image through the up-
per abdomen shows a large infiltrating intermediate-risk hyperintense liver mass (arrows). (e) Coronal postnatal CT image obtained
shortly after birth shows the large heterogeneous mass (black arrows) in the central portion of the liver and the additional metastasis
(white arrows) in the pelvis. (f) Axial postnatal CT image also shows the bilateral adrenal masses (arrows). This case was determined
to be that of a stage IV intermediate-risk neuroblastoma. The patient underwent chemotherapy, with an excellent response at follow-
up 2 years after the birth.

Normally, the fetal gallbladder can be seen as
early as 13 weeks gestation and usually by 14–15
weeks gestation, and it can be identified as a cystic
structure to the right of the intrahepatic umbili-
cal vein and inferior to the liver (67,71,74,75).
Visualization of the fetal gallbladder is now part of
the routine detailed fetal anatomic survey exami-
nation. In the second trimester, a nonvisualized
gallbladder, defined as the inability to identify the
gallbladder at two US examinations performed 1
week apart, occurs in approximately one in 875 fe-
tuses. The gallbladder continues to grow for up to
36 weeks (67,71,75). The severity of the condition
causing the absent gallbladder varies widely, with
the differential diagnosis including biliary atresia,
cystic fibrosis, ectopic gallbladder, and gallbladder
agenesis (71). A nonvisualized gallbladder with ad-
ditional associated abnormalities such as hepato-
megaly increases the risk of biliary atresia three- to
sixfold, with approximately 8% of affected patients
having biliary atresia and the remaining patients
having predominantly cystic fibrosis or enteric
abnormalities (67,71).
Without associated abnormalities, approxi-
mately 3%–5% of patients with a nonvisualized
gallbladder have biliary atresia. The majority
of patients with an isolated nonvisualized gall-
bladder are later found to have a gallbladder
or benign gallbladder agenesis (67,71,75). In
newborns, biliary atresia can be confirmed on the
basis of an absent or abnormal gallbladder mor-
phology and a thickened triangular cord, defined
as greater than 3.4 mm of echogenicity adjacent
to the right or left portal vein, which represent fi-
brotic changes (68,69). Early treatment can help
maintain the function of the native liver and help
decrease the need for early hepatic transplanta-
tion, decreasing morbidity and mortality (68,73).
Fetal Anemia
Fetal anemia (Fig 11) can cause hepatomegaly
owing to one of two mechanisms: hydrops-related
liver congestion and liver engorgement from ex-
tramedullar hematopoiesis. As the cardiac output
increases to compensate for the anemia, high-out-
put heart failure and hydrops may result (76). In
RG  •  Volume 40  Number 2 Jensen et al  601

Figure 10.  Biliary atresia in a fetus at 30 weeks gestation. (a) Transverse US image through the
upper abdomen, with the spine on the right, shows an enlarged hypoechoic liver (thick arrows)
with innumerable punctate and linear echogenicities (thin arrows), suggesting hepatomegaly and
periportal fibrosis. No gallbladder is visualized in the expected region (oval). (b) Sagittal US image,
with the chest at the superior aspect, also shows the hypoechoic enlarged liver (thick arrows) with
echogenic punctate and linear foci (thin and double-headed arrows). (c) Sagittal T2-weighted MR
image through the fetus, with the head at the superior aspect, shows hepatomegaly (). Note
how the liver extends into the fetal pelvis and beyond the inferior pole of the right kidney (arrows).
Despite an active search, the gallbladder was not seen in this fetus with any MRI sequences or at
any US examinations during the pregnancy.

demise, serial maternal titer measurements are

addition, extramedullary hematopoiesis can affect
the degree of hepatomegaly owing to the embryo-
logic origin of hematopoietic stem cells within the
liver of the developing fetus (77,78).
The cause of fetal anemia can be categorized
as immune mediated or nonimmune mediated.
Among the causes of immune-mediated anemias,
rhesus D sensitivity is the most common, although
other minor antigens or proteins also can cause
maternal sensitization. Alloimmunization occurs
after the mother becomes sensitized to fetal red
blood cell antigens and subsequently develops
maternal antibodies that cross the placenta and
cause fetal red blood cell hemolysis and, in turn,
fetal anemia. When the anemia is severe, hydrops
can result. To prevent hydrops and the risk of fetal
performed in sensitized maternal patients, and
if critical levels of rhesus antigen D are present
(≥1:32 for anti-RhD), Doppler US of the MCA is
performed in combination with standardized peak
systolic velocity measurements to monitor for fetal
anemia (Figs 2d, 3f, 11e) (79–81).
Previously, serial amniocentesis was performed
to quantify bilirubin levels as a measure of he-
molysis. However, MCA Doppler US has essen-
tially replaced invasive procedures for diagnosis
and assessment of severe anemia (82–84). Once
the Doppler US MCA peak systolic velocity
is greater than 1.50 multiples of the median,
intrauterine transfusion is considered (79,85).
The key to accurate assessment for possible fetal
anemia with MCA Doppler US is the use of the
appropriate sampling technique, which includes
identifying the circle of Willis, placing the Dop-
pler gate near the origin of the MCA with a small
sample volume, using a 0° angle of insonation,
and obtaining serial measurements without fetal
breathing or motion (80,81).
Nonimmune causes of fetal anemia include in-
herited anemias (eg, α or β thalassemia), congeni-
tal infections (eg, parvovirus), fetal hemorrhage
(eg, due to fetal or placental tumors, trauma),
and a twin anemia-polycythemia sequence (in
the case of monochorionic twins). Inheritance of
α or β thalassemia is autosomal recessive, and if
the most severe form of α thalassemia is present,
the anemia manifests in utero with cardiomegaly,
602  March-April 2020 radiographics.rsna.org

Figure 11.  Primary fetal anemia caused by a homozygous gene deletion in a fetus at 21 weeks 3 days gestation. (a) Sagittal US im-
age, with the chest at the superior aspect of the fetal body, shows hepatomegaly (), with the liver extending into the pelvis. There
is also pleural effusion (thick arrow) and more subtle evidence of hydrops, trace ascites (thin arrow), and body wall edema (arrow-
heads). (b) Transverse US image at the level of the liver (), with the spine on the right, shows a mildly coarse hepatic echotexture
and confirms the presence of trace ascites (calipers). (c) Four-chamber US view of the heart shows cardiomegaly, with the heart oc-
cupying more than half the volume of the chest, and bilateral pleural effusions (arrows). LT = left, RT = right. (d) Longitudinal color
Doppler US image of the posterior uterus shows a thickened and enlarged placenta, which is suggestive of hydrops. (e) Owing to the
US findings, spectral Doppler US evaluation of the MCA was performed and revealed the peak systolic velocity (Vel) to be elevated
for the gestational age of this fetus and thus suggestive of severe fetal anemia. An intrauterine blood transfusion was performed, and
the hydrops subsequently resolved.

hepatosplenomegaly, elevated MCA Doppler
peak systolic velocity, and potentially hydrops.
With this most severe form of thalassemia, all
four α-globin alleles are deleted and hemoglobin
Bart, which cannot effectively transport oxygen,
forms. Extramedullary hematopoiesis occurs in
the liver and spleen as a mechanism that com-
pensates for the anemia. Consequently, hepa-
tomegaly can be a predictor of affected fetuses
before the development of hydrops (86), and ex-
tramedullary hematopoiesis is an additive reason
for hepatomegaly (78,87).
Conclusion
Fetal hepatomegaly is an important finding asso-
ciated with many diagnoses that have significant
clinical implications. Hepatomegaly should be
considered if the fetal liver appears to be enlarged
at screening US and the fetal liver measure-
ment indicates a liver length greater than the
95th percentile. Fetal hepatomegaly can be seen
in association with fetal infection, trisomy 21,
liver storage and deposition diseases, syndromes,
tumors, biliary atresia, and anemia. With some of
these diagnoses, such as syphilis and trisomy 21,
antepartum surveillance of the liver is important
for assessing fetal health and planning delivery or
another fetal intervention.
The cause of fetal liver enlargement may be a
primary insult such as hepatitis related to infec-
tion, deposition of iron or lysosomes, or primary
tumor, or a secondary process such as extramed-
ullary hematopoiesis, edema related to hydrops,
or metastatic tumor. We highlight the importance
of considering diagnoses such as gestational al-
loimmune liver disease, infection, and syndromes
in fetuses with nonimmune-mediated hydrops or
unexplained ascites and encourage sonographers
RG  •  Volume 40  Number 2 Jensen et al  603
to measure the liver in these scenarios. In addi-
tion, we suggest that a diagnosis of hepatomegaly
is important and may aid the clinician in making
an accurate specific diagnosis.
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