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THE ANATOMICAL RECORD 249:389–398 (1997)
Developing Human Biliary System in Three Dimensions
VIJAYALAXMY VIJAYAN1* AND CAROLYN E.L. TAN2
of Paediatric Surgery, Singapore General Hospital, Singapore
2Department of Paediatric Surgery, Singapore General Hospital, Singapore
1Department
ABSTRACT
Background: In the development of the human biliary
system, although the extrahepatic bile ducts develop from the embryonic
hepatic diverticulum, there is increasing evidence to suggest that the
intrahepatic bile ducts originate within the liver from the ductal plate.
The ductal plate develops as a sheath of primitive biliary epithelium in the
mesenchyme along the portal vein branches. Through an orderly process
of selection and deletion, the ductal plate is remodelled into the adult
system of anastomosing tubular bile ducts. The ductal plate remodelling
process occurs at the porta hepatis between 11 and 13 weeks of gestation
and progresses towards the periphery of the liver.
Methods: In this project, for the first time, we have used computerised
three-dimensional reconstruction techniques to visualise the developing
human biliary system. Paraffin-embedded tissue from eight human embryos or fetuses between 5.5 and 16 weeks of gestation were serially
sectioned, and their images were aligned, digitised, and used for threedimensional reconstruction.
Results and Conclusions: Three-dimensional images of the extrahepatic
and the intrahepatic biliary systems were obtained, and the following conclusions were drawn. (1) The intrahepatic biliary system, both at the porta
hepatis and within the liver, developed from the ductal plate through a
consistent pattern of remodelling. (2) Prior to the remodelling process, the
ductal plate was of similar morphology irrespective of site and gestation.
(3) The extrahepatic biliary system was in direct luminal continuity with
the developing intrahepatic biliary system throughout gestation and did
not show the presence of a ‘‘solid stage’’ in any of the embryos or fetuses
studied. Anat. Rec. 249:389–398, 1997. r 1997 Wiley-Liss, Inc.
Key words: ductal plate; bile ducts; biliary development; liver embryology
In the development of the human biliary system, the
extrahepatic and intrahepatic systems differ in their
origin. The extrahepatic bile ducts (EHBD) and the
liver arise from the embryonic hepatic diverticulum,
which is a ventral projection from the developing
foregut (Severn, 1971, 1972).
Several theories have been proposed for the development of the intrahepatic bile ducts (IHBD) that link the
bile canaliculi and the EHBD. One that is gaining
increasing support is that the IHBD arise from the
ductal plate, a sheath of primitive biliary epithelium
that develops in the mesenchyme along the portal vein
branches (Desmet, 1985; Terada and Nakanuma, 1995).
Through an orderly process of selection and deletion,
the ductal plate is remodelled into the anastomosing
system of tubular bile ducts seen in the adults (Fig. 1).
This ductal plate remodelling process starts at the
porta hepatis, where it is said to occur between 11 and
13 weeks of gestation, and progresses towards the
periphery of the liver (Tan and Moscoso, 1994a,b).
Thus, the porta hepatis is the crucial region where the
EHBD merges into the IHBD. According to some reports, remodelling along the more distal portal vein
r 1997 WILEY-LISS, INC.
branches may even occur after birth (Van Eyken et al.,
1988; Woolf and Vierling, 1993).
The incorporation of computers in microscopy has
opened the exciting new possibility of visualising developing organs in three dimension. With serial sections, it
is now possible to reconstruct the entire organ under
study. In manually drawn reconstructions, the observer’s preconceived ideas may affect the results, but
computer-generated three-dimensional (3-D) reconstructions can eliminate such errors. In the references cited
above, the fetal biliary system and the ductal plate
remodelling have been studied using manual reconstructions of serial sections. In the present study, we used
computerised 3-D reconstruction techniques to visualise the developing human biliary system.
Contract grant sponsor: Department of Clinical Research, Ministry
of Health, Singapore; Contract grant sponsor: Department of Paediatric Surgery, Singapore General Hospital, Singapore.
*Correspondence to: Vijayalaxmy Vijayan, Department of Paediatric Surgery, KK Women’s and Children’s Hospital, 100 Bukit Timah
Road, Singapore 229899.
Received 11 December 1996; Accepted 10 April 1997
390
V. VIJAYAN AND C.E.L. TAN
TABLE 1. Fetuses and embryos used in the present study
Fetuses/embryos
F25
F16
F46
F4
F7
F28
F47
F45
Gestational age
(weeks)
Foot length
(mm)
5.5
7
8.5
11
11
12
13
16
1
1
4.2
6
7
10.5
11.16
19.7
1These embryos were staged based on external morphology.
cies for psychosocial reasons. Approval was obtained
from the hospital’s ethical committee. All embryos and
fetuses were karyotyped and were normal 46XY or
46XX. The specimens were immediately fixed in 4%
buffered paraformaldehyde for 24 hr at room temperature, transferred to 15% sucrose in phosphate buffered
saline, and left at 4°C until embedding in paraffin wax.
The developmental stages of the embryos were determined according to the method of O’Rahilly and Müller
(1987) and the fetuses were staged according to the
method of Streeter (1920).
3-D Reconstruction
Fig. 1. Diagrammatic representation of the formation of an intralobular bile duct within a portal tract. To simplify the illustration the
hepatic artery branch and mesenchymal tissue have not been drawn.
A: A single layer of biliary cuboidal epithelium; the ductal plate has
developed at the liver parenchyma–mesenchyme margin. B: The
ductal plate is separated from the hepatic margin by proliferating
mesenchymal tissue. C: Continued mesenchymal proliferation (arrowheads) has pushed the ductal plate farther away from the hepatic
parenchyma. The ductal plate has duplicated, and luminal spaces
have appeared between the two layers of cuboidal epithelium. D: One
portion of the ductal plate is actively remodeled by surrounding
mesenchyme into a tubular bile duct (*), while the rest of the
redundant ductal plate structures are being deleted. E: The ductal
plate remodeling process is complete, and an intralobular bile duct has
developed, whereas its biliary precursor, the ductal plate, has disappeared. The mesenchymal cuff around the definitive bile duct is not
shown. (Figure reproduced with permission from Tan et al., 1995,
Pathol. Int. 45:815–824, Fig. 1.)
MATERIALS AND METHODS
Embryos and Fetuses
Eight normal human embryos and fetuses of 5.5–16
weeks gestation were studied in this project (Table 1).
All embryos and fetuses were obtained from healthy
mothers undergoing elective termination of pregnanAbbreviations
b/bd
cbd
cd
chd
dp
gb
h
lhd
m
ph
pv
rhd
bile duct
common bile duct
cystic duct
common hepatic duct
ductal plate
gall bladder
liver parenchyme
left hepatic duct
mesenchyme
porta hepatis
portal vein
right hepatic duct
Serial sections of 5 µ thickness were cut, and every
third section was stained with toluidine blue and used
in the 3-D reconstruction. Digitisation was done through
a CCD camera (Progressive Research 3012, Carl Zeiss,
Germany), which was attached to either a microscope
(Axiophot, Carl Zeiss, Germany) or a AF Micro-Nikkor
60 mm f/2.8 D lens (Nikon), depending on the magnification required.
Sections were aligned using a RGB monitor connected to the VIOB output of the IBAS 2.5 system
(Kontron Elektronik, Germany). To align an image, the
preceding image was converted into an overlay, and the
current image was aligned according to the overlay.
Alignment was done by using clearly visible structures
in the images as references. Each section was stored as
a separate image of 512 3 512 pixel resolution with 256
(0–255) grey levels. The biliary structures and blood
vessels were manually traced in each image and the
other structures were erased, and the traced image was
scaled to grey levels 0–254. The lumina within the
biliary structures were assigned a grey level of 255. The
voxel-based 3-D reconstruction technique of distance
shading was used to generate 3-D images (Moss, 1992).
For each embryo or fetus, the EHBD, consisting of the
common bile duct (cbd), the gallbladder (gb), the cystic
duct (cd), and the common hepatic duct (chd), was
reconstructed. The IHBD, consisting of biliary structures at the porta hepatis, was reconstructed in all
embryos and fetuses, and where possible the biliary
structures proximal to the porta hepatis also were
reconstructed. In all the specimens, reconstructions
along the luminal spaces of the biliary structures also
were generated to get a 3-D view of the lumen. Wherever possible, the veins were included in the reconstructions. A median filter of matrix size 3–7 was applied to
smooth the edges of the final 3-D image. Details of the
DEVELOPING HUMAN BILIARY SYSTEM IN 3-D
391
Fig. 2. EHBD and its lumen. A: The 3-D image of a 5.5-week embryo
showing the cbd and a funnel-shaped widening of the cbd at the porta
hepatis. The cd joins the cbd at the ph with a very short chd in this
specimen. The gb points upwards in this specimen, probably due to a
fixation artefact (Fig. 4 shows the ph region at higher magnification).
B: Photomicrograph of a transverse section through the cbd (arrow)
just distal to the ph of a 5.5-week embryo, showing the presence of a
clear and patent lumen. C: The 3-D image of a 7-week embryo in which
the gb is well formed and the chd ends in fingerlike ductal plate
structures at the ph. D: The 3-D image of the lumen corresponding to
C. Scale bar 5 50 µ.
methodology have been reported elsewhere (Vijayan
and Tan, 1995, 1996).
through the stages of remodelling until the adult
configuration is achieved.
RESULTS AND DISCUSSION
Extrahepatic Bile Ducts (Figs. 2, 3)
Reports about the development of the human biliary
system, particularly the ductal plate remodelling, have
been based on manual reconstruction of serial sections.
The present study is the first computer-generated 3-D
reconstruction of the developing human biliary system
The EHBD of all eight embryos or fetuses at 5.5–16
weeks of gestation were reconstructed. The EHBD was
clearly visible and had a continuous and patent lumen
through its entire length in all the specimens studied.
This observation confirms the absence of a ‘‘solid stage’’
392
V. VIJAYAN AND C.E.L. TAN
Fig. 3. The 3-D reconstructions of the EHBD and its lumen. A: An 8.5-week fetus showing the EHBD and
(B) its lumen. C: An 11-week fetus showing the EHBD and (D) its lumen. In all the gestations, a
continuous lumen is present throughout the EHBD.
during the development of the cbd, as previously reported (Tan and Moscoso, 1994a).
Intrahepatic Bile Ducts
At the porta hepatis (Figs. 4–11)
There is little controversy regarding the development
of the EHBD, which arises from the embryonic hepatic
diverticulum (Severn, 1971). However, there are two
main theories about the origin of the IHBD. One is that
the IHBD originate from the EHBD at the porta hepatis
and grow into the liver in an infiltrative manner
(Hammar, 1926; Koga, 1971). The other, has accumulated compelling evidence in recent years, is that the
IHBD develop from within the liver from the ductal
plate, which through a process called ‘‘ductal plate
remodelling’’ matures into the tubular anastomosing
biliary tree of the adult (Desmet, 1985; Jorgensen,
1977; Terada and Nakanuma, 1995; Van Eyken et al.,
1988).
DEVELOPING HUMAN BILIARY SYSTEM IN 3-D
393
Fig. 4. A 5.5-week embryo. A: Photomicrograph of a transverse
section at the porta hepatis showing the chd (short arrow) and the dp
structures (long arrows) attached to the chd. The separation (*)
between the chd and the liver parenchyma is artefactual. B: A 3-D
image of a 5.5-week embryo at the porta hepatis showing ductal plate
structures attached to the chd/cbd. Scale bar 5 50 µ.
Fig. 5. A 7-week embryo A: Photomicrograph of a transverse section
at the level of the porta hepatis showing the chd (short arrow) and
fingerlike dp structures (long arrows) attached to it. Tiny luminal
spaces are seen in the dp. B: The 3-D images show early dp structures
attached to the chd, projecting into the liver like fingers of a hand.
Scale bar 5 µ.
All the specimens in this study showed the presence
of ductal plate structures at the porta hepatis. In the
5.5-week embryo (embryo F25; Fig. 4), early ductal
plate structures were seen at the porta hepatis. The cbd
showed a funnel-shaped widening at the porta hepatis,
to which ductal plate structures were attached. At 7
weeks of gestation (embryo F16; Fig. 5), early ductal
plate structures with luminal spaces were seen at the
porta hepatis. In three dimensions, they were seen as
fingerlike projections continuous with the chd at the
porta hepatis. Proximal to the porta hepatis, within the
liver, no ductal plate structures were observed in these
394
V. VIJAYAN AND C.E.L. TAN
Fig. 6. A: The 3-D reconstruction at the porta hepatis of an 8.5-week
fetus showing the ductal plate structures closely hugging the portal
vein branch. The chd is continuous with the ductal plate structures. B:
Reconstruction of the corresponding luminal spaces showing that
there is luminal continuity between the chd and the ductal plate
structures. Biliary structures are shown in yellow, and the portal vein
branch is shown in grey.
Fig. 7. A 3-D reconstruction at the porta hepatis of two 11-week
fetuses: A: Fetus F4 show the chd in continuity with ductal plate
structures along the vein. One prominent tubular bile duct is beginning to form (arrow). B: Fetus F7. In this fetus, two tubular branches
of the chd can be seen, which are in continuity with the ductal plate
structures along the two branches of the vein. Biliary structures are
shown in yellow, and the portal vein branches are shown in grey.
early embryos. Other investigators have reported
the appearance of the ductal plate at the porta hepatis
at 6–9 weeks gestation (Van Eyken et al., 1988; Tan
and Moscoso, 1994a), which suggests some variability
in the onset of ductal plate formation at the porta
hepatis.
DEVELOPING HUMAN BILIARY SYSTEM IN 3-D
Fig. 8. Photomicrograph of a transverse section through the ductal
plate in an 11-week fetus: Ductal plate structures (arrows) in the
mesenchyme surround a portal vein branch. Discontinuous luminal
spaces are seen in the ductal plate (*). Scale bar 5 50 µ.
Fig. 9. A 3-D reconstruction at the porta hepatis of a 12-week fetus.
The adult pattern of tubular left and right hepatic ducts (arrows) can
be seen with some ductal plate remnants still attached to them. Vein
and gb are not included in this reconstruction.
The ductal plate consisted of a network of abundant,
flat biliary structures hugging and closely following the
portal vein branch. However, within the ductal plate,
the luminal spaces formed a network connected at some
395
Fig. 10. A 3-D reconstruction at the porta hepatis of a 13-week fetus.
At this gestation, the adult pattern is seen clearly. The left and right
hepatic ducts (arrows) and their branches are seen. Biliary structures
are shown in yellow, and the portal vein branches are shown in grey.
Gallbladder is not shown.
Fig. 11. A 3-D reconstruction at the porta hepatis of a 16-week fetus.
Well-defined tubular bile ducts of the adult configuration are seen with
first- and second-generation branches of the chd. Biliary structures
are shown in yellow, and the portal vein branches are shown in grey.
Gallbladder is not shown.
places and isolated at others, similar to that described
in the mouse embryo (Shiojiri and Mizuno, 1986). At 8.5
weeks gestation (fetus F46; Fig. 6), the curved platelike
network encompassed half the circumference of the
vein. The 3-D reconstruction along the luminal spaces
396
V. VIJAYAN AND C.E.L. TAN
Fig. 12. Several 3-D reconstructions proximal to the porta hepatis.
A: An 11-week fetus and B: a 12-week fetus show ductal plate
structures along a portal vein branch within the liver. C: A 16-week
fetus shows a tubular, well-defined interlobular bile duct along a
portal vein branch. Biliary structures are shown in yellow, and the
portal vein branches are shown in grey.
of the ductal plate and the lumen of the chd showed that
they were in direct luminal continuity at the porta
hepatis, a feature clearly observed in all stages of
gestation. At 8.5 weeks of gestation, the treelike pattern of the adult-type bile ducts was not seen, suggesting that the biliary structures at the porta hepatis had
not yet been remodelled from the ductal plate configuration to tubular bile ducts.
Two fetuses were studied at 11 weeks gestation
(fetuses F4 and F7; Fig. 7). Abundant ductal plate
structures were seen that morphologically resembled
those of the 8.5-week fetus. In fetus F4, the chd was in
direct continuity with the ductal plate structures, among
which one tubular bile duct was already beginning to
form. Figure 8 shows a photomicrograph of the ductal
plate in transverse section. In fetus F7, a more adultlike
pattern was seen with tubular left and right branches
(first-generation branches) of the chd. The two branches
were continuous with ductal plate structures seen
poximally along the two branches of the vein. The foot
length measurements of the two fetuses show that F7 is
older than F4, thus explaining the more adultlike
DEVELOPING HUMAN BILIARY SYSTEM IN 3-D
pattern at the porta hepatis in fetus F7. Many normal
variations in the right and left hepatic duct morphology
may be due to the variations in the remodelling process
at the porta hepatis (Tan and Moscoso, 1994a).
At 12 weeks of gestation (fetus F28; Fig. 9), the
ductal plate at the porta hepatis had been remodelled
almost fully into adult configuration. Tubular left and
right branches (first-generation branches) of the chd
were seen clearly; however, remnants of ductal plate
were still seen attached to them. Further proximally
into the liver, the bile ducts were in continuity with
ductal plate structures.
By 13 weeks (fetus F47; Fig. 10) and 16 weeks (fetus
F45; Fig. 11) of gestation, the remodelling had produced
not only left and right hepatic (first generation) ducts
but also second-generation ducts that were branches of
the hepatic ducts. The adult pattern of bile ducts was
seen clearly at the porta hepatis at these gestations.
Proximal to these definitive ducts, the biliary system
remained in the ductal plate configuration, and the
tubular bile ducts were continuous with these ductal
plate structures.
These results confirm previous reports that the intrahepatic biliary system develops within the liver from
the primitive fetal biliary structure, the ductal plate,
and not by branching growth from the EHBD into the
liver. It also establishes that the process of ductal plate
remodelling changes the platelike ductal plate into
tubular bile ducts of the adult, starting at the porta
hepatis and progressing into the liver with gestation.
The exact intrauterine period during which the remodelling occurs at more proximal regions of the intrahepatic biliary system is not entirely clear. In rat embryos, the remodelling continues after birth to achieve
the adult configuration (Gall and Bhathal, 1989). Similarly in humans, Woolf and Vierling (1993) suggested
that, at the periphery of the liver, biliary remodelling
may continue after birth. In our series of fetuses, the
remodelling process is complete at the porta hepatis by
13 weeks, which is similar to the 11–13-week crucial
period suggested by other reports (Tan et al., 1994).
Proximal to the porta hepatis (Figs. 12, 13)
Biliary structures proximal to the porta hepatis, well
within the liver, were also reconstructed. The primitive
intrahepatic biliary structures within the liver were
morphologically identical to the ductal plate structures
seen at the porta hepatis before the onset of ductal plate
remodelling. The biliary structures along the portal
vein branches showed ductal plate configuration in the
two younger fetuses at 11 and 12 weeks of gestation. As
gestation progressed, the ductal plate was remodelled
into tubular bile ducts, which could be observed by 16
weeks. Figure 13 shows a transverse section of a
definitive intralobular bile duct in a portal tract from
the 16-week fetus. Before the start of the remodelling
process, the ductal plate structures remain consistent
in morphology, irrespective of (a) site within the liver,
i.e., at the porta hepatis or more proximally, and (b)
gestational age.
The mechanism by which the flat lacelike ductal
plate is remodelled into a treelike pattern of tubular
bile ducts has been the topic of much speculation. A
recent report has shown that balanced cell proliferation
and apoptosis play a role in the remodelling (Terada
397
Fig. 13. Photomicrograph of a transverse section through a portal
tract in a 16-week fetus. A tubular definitive bile duct (arrow) is shown
within a portal tract. Scale bar 5 50 µ.
and Nakanuma, 1995). Cytokines such as transforming
growth factor a1 play a role in the remodelling process
(Terada et al., 1994). Reports have shown that the
immunolocalisation pattern of transforming growth
factor b1 within the biliary epithelium changes as the
ductal plates matures into definitive bile ducts (Tan et
al., 1995). These reports suggest that molecular and
cellular signals are involved in the ductal plate remodelling process. The mesenchyme also plays an important role in the development of the intrahepatic bile
ducts (Shiojiri and Nagai, 1992), which has been shown
by the transplant experiments of Shiojiri (1984), in
which the immature mouse hepatocytes differentiated
into IHBD cells only when transplanted into the subcutaneous connective tissue and not into the testes of
newborn mice. A timed inductive signal appears to
trigger the wave of ductal plate remodelling from the
porta hepatis outwards to the rest of the IHBD, the
exact nature and origin of the which remains unclear at
this point.
In summary, the IHBD at the porta hepatis and
within the liver arise from the ductal plate, which is the
primitive fetal biliary system, through an orderly process of selection and deletion termed ‘‘ductal plate
remodelling.’’ Before the start of the remodelling process, the ductal plate is consistent in morphology
irrespective of site and gestation. The EHBD are in
direct luminal continuity with the developing IHBD
throughout gestation. Furthermore, the EHBD did not
show the presence of any ‘‘solid stage’’ during its
development.
ACKNOWLEDGMENTS
We thank Dr. Henry H. Cheng and Dr. Ann Tan for
contributing specimens to this study, Ms. Angela Ho for
398
V. VIJAYAN AND C.E.L. TAN
karyotyping the specimens, and Dr. Shanthi Wasser
and Dr. A Vijayan for proof reading the manuscript.
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