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Subdivision of hexagonal liver lobules into a structural and functional unit. Role in hepatic physiology and pathology

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SUBDIVISIOS OF HEXAGOSAL lJT7ER LOBUTJES
ISTO A STRUC'Tt'RAL AND FVIV('T1ONAL UXIT "
ROLE IB HEPATIC PHYS IOL OGY A&-;L) PAT€IOT,OGY
A . M. RAPPAPORT, Z. J. BOROWY, W. M. LOUGHEED
A X D W. N. LOTTO
Depart7ne?~tof Pliysiolngy nwd Bantiiig and Best Depni tineiit of Medical R e s C a ~ ~ h ,
Unzwisitjl nf l'oroiito, Toronto, Canada
E L E V E S FIGURES
While the textbooks of histology present the hexagonal
lobule as the ultimate unit of the liver, investigations and
discussions about hepatic structure are still being continued
assiduously.
Riernan's (1833) geometrical concept of thc liver architecture, although generally accepted, has not been shared by
all invcstigatous in this field. Sabourin (1888) questioned the
hexagonal lohule centered around the terminal hepatic vein.
Hc emphasized the exocrine function of the liver, and described a secretory liver unit which represents the amount
of liver parenchyma that is drained by the bile canal of a
portal triad. Mall ('06) described the portal unit, and his
view was adopted by Arey ('32) and Opie ('44). Recently
Elias ( '49a, b) put forward the theory of the liver being composed of parenchymal plates tunnelled by a nett~~ork
of lacunae
(' 'labyrinthus hepatis"), but, f o r orientation within the hepatic labyrinth, he uses Kiernan's concept of the liver lobule
and his terminology.
This work was supported in p a r t by a grant from the Defense Researeli Board
of Canada.
A s p o p s i s of this work w a s presentcd at the Elerenth Conference on Liver
I n j u l ? slmiisored 1 1 ~the Josiah Macy, J r . Foundation, S e w P o r k City, M a y 30,
1952. The hepatic structural unit was then called the 'lirer aciiius."
11
12
RAPPAPORT, BOROWY, LOVGHEELI A N D LOTTO
3licroscopic observations of the hepatic circulation i?i L‘ i co
have provided valuable inforination about the liver architecture, but there is difficulty in coi~elatiiigthese observations
with the still classical idea of the hexagonal lobule. It is
observed that the blood enters the liver units through the
terminal afferent portal and arteiial twigs, and flows through
surrounding tissue which, however, is not orientated about
one of the central veins. Usually the blood from one such pair
of afferent vessels streams into the siiiusoids of ail area that
extends into sectors only of several neighboring hexagonal
fields. Thus the hexagonal pattern is not a t all conspicuous
irz vivo (Kniscly, ’52).
F o r students of histology and physiology it is a l w a y difficult to uiiderstand why, in the liver, the afferent blood vessels
and the escwtory ducts a r e situated at the periphery of the
glandular unit while the draining venous vessel is in its center.
Many liiiotty problems a r e encountered by the histopathologist in dcscriliing and understanding the lesions he ohservca
in the hexagonal liver lohule. It is known through clinic and
experiment that ischemic necrosis has its most deleterious
effects at thcl periphery of an organ : nevertheless the pathologist will h a r e to report as “central necrosis” the destructive
lesions around the radicle of the hepatic veins.
Because the hexagonal lobules a r e supposedly the ultiniatc
units of the liver, and represent in miniature the functions
of the entire organ, in our experinleiits with hepatic ischemia
we anticipated that these lobules would show lesions at their
periphery. However, they did not hehave a s expected, but
showed “central ” lesions instead. We questioned, therefore,
Kiernan’s concept of the hepatic lobule and investigated it
by the following methods.
METHODS
F r e s h livers of rabbits and dogs were washed by perfusion
with lukewarni saline (sodium nitrite solution, 0.5%) through
the portal vein. Cannulas were introduced into the two main
branches of the portal vein. Ranvier’s carmine gelatin mass
H E P A T I C S TR U C T U R A L A N D FGXCTIONAL UNIT
13
(Lee, ‘ 3 7 ) was injected through one cannula while a gelatin
mass of the same viscosity colored with India ink was injected
simultaneously through the other. To make sure that both
injections were made a t the same pressure, two syringes containing the gelatin masses were mounted on a baseboard and
their pistons pushed a t the same time by a block of wood
sliding on the base. The same technic was used for injection
of the liver via the two branches of the hepatic artery.
Other livers were injected through the biliary ducts. To
avoid parenchymal damage that might follow the increased
pressure in such a closed system, the biliary ducts were not
first washed with saline. Injection of the bile channels is more
difficult to carry out than that of the blood vessels. I n spite
of the anastomoses between the bile ducts, there is not such
free flow of the iiijectioii mass as through the sinusoids into
the hepatic veins. Severthcless the gelatin mass had to be
introduced with oiily slight pressure.
Ti’ith the inflow of the gelatin masses the liver became
colored and showed the black and red dyes meeting in intermediate zones. It was to be expected that the injection mass
travelling along a portal channcl, for example, would find its
terminus in a microscopical area belonging to a terminal
portal branch. Because of the simultaneous inflow, under
the same pressure, of the differently colored mass through
a neighboring terminal portal branch, the spread of the color
by anastomotic sinusoids from one terminal area to another
would be minimized.
After injection, the livers were put in 10% formalin for
24 hours. Tissue blocks were cut from the intermediate zones
where the red and black colors intermingled equally. Sometimes tissue samples were taken from zones where both colors
delimited each other sharply. Frozen and cleared sections
were made and stained with hematoxylin.
RESULTS
The tissue blocks showed one branch of the vein (artery
or bile duct) bringing in black color (fig. 4, B) and another
14
R A P P A P O R T , KOROWY, LOT-GHEED A S D LOTTO
branch red color (fig. 4, R ) . llicroscopically the distribution
of the dye did not respect the hexagonal pattern. I n spite
of the numerous anastomoses arid branchings of the sirlusoidal
vessels, many hexagonal lobules were broken dom7n into smaller
differently colored fields. Grape-like areas of uniform color
were oliserved arouiid certain termiiial portal branches which
conveyed the correspontling dye ; each occupied adjacent sectors of two hexagonal fields that were of different color.
Similarly colored areas were obtained by injection of two
branches of the hepatic a r t e r y or bile duct. Thus the hexagonal fields were broken down and subdivided into smaller
structural units arranged around the afferent terminal vessels
and the efferent teimiiiial bimich of the bile duct.
What we call the hepatic structural unit (fig. 3, LA, L1,Al)
is the small, berry-like, Inass of parenchyma irregular in size
and shape situated around the trio of terminal branches of
portal vein, hepatic a r t e ~ yand bile duct lwanching out from
a small portal space.
The periphery of the structural unit yeaches two central
veins, and thus two af'fcrent vessels a r c drained by two o r
inore veins, while in tlie hexagonal loliulc at least 1 2 af'fercnt
vessels a r e believed to be drained by one vein.
A regular hexagoiial field a s visualized in microsections is
fornied by halves of 6 structural units, while the other halves
belong to the adjacent liexagoiial fields. However, in reality,
the structural units a r e not divided into halves by the hexagonal fields - just tlie contrary ; tlie hexagonal field is broken
down by different liver units. This is demonstrated in figure
5, which shows the liver of a rabbit injected through portal
branches. I n the right lower corner there is a portal triad
through which the carmine inass penetrated the hexagonal
field. A clear cut structural unit extends from the terminal
hepatic (central) rein in the left lower corner to the other
central vein at the upper margin of the picture. The area
not colored by India ink is c e n t e i ~ daround the so-called
interlobular structures composed of the trio of terminal vascul a r hraiichcs and temiiiial hile duct. The latter is seen cut
HEPATIC S T R V C T Y n A L AXTI F 1 7 S C T I O S h L I T S I T
15
longitudinally iii this section. A similar field extends from
the portal triad to the right and to the upper central vein.
These small areas surrounding the terniiiial branches of the
portal vein, hepatic artery and bile duct represent secretory
units.
I n figure 6, the hexagonal field was broken domi into different sectors by the injection of differently coloiaed masses
through two branches of the hepatic artery. Black gelatinmass was found in one small arterial branch ( B ) , red in
the other ( R ) , while both colors weye found in the central
vein (CV). The colors delimit different sectors in one hesagoiial field.
A similar picture was obtained by injecting two branches
of the bile duct (fig. 7 ) . One branch conveying black color
into red hexagonal fields can be clearly distinguished. The
black injection mass spreads in an area which extends froni
one central vein to another. Thus the smallest structural
unit is not just a niertl physiological conception, but a histomechanical reality.
T h e blood m p p 1 1 ~of the, lzepcrtic sfrtictzrrcll uizit
The blood vessels supplying the hepatic units are arranged
in a definite pattern. Indeed the number and shape of the
structural units are best determined by following the course
of the injected afferent vascular channels. These arterial and
portal vessels run in the portal spaces and are characteristically surrounded by sheaths of fibrous tissue. Their course
is mainly parallel to the central veins. From the portal spaces
terminal arterial and portal venous twigs branch out at different levels and in a tridimensional way (see fig. 2 and fig. 3).
Their course is perpendicular to the central veins and together with the accompanying terminal bile ductules they
form the axes of the structural units. Each is arching rather
than running in a straight line. Therefore the spatial distribution of these terminal twigs oiily sketches hexagonal
fields. The many ways of spreading out, sidebranchinc and
16
BAPPAPORT, BOROTVY, LOI:GHEED
A S D LOTTO
ariastomosiiig of the terminal vascular chaniiels are also
indicated in figure 2. It looks as if the blood coming up in
pulsating jets through the terminal twigs into the sinusoids,
and, dispersing like a fountain, waters and nourishes the
parenchyma of the hepatic units in several hexagonal fields.
The sinusoidal glonius in which arterial and portal blood are
mixed is woven around these liver cords (or plates) which
Fig. 1 The blood supply of the hepatic structural unit: The structural unit
occupies adjacent sectors of neighboring hexagonal fields. Zones 1, 2, a u d 3
respectively represent areas supplied with blood of first, second, and third quality
with regard t o oxygen and nutrients. These zones center about the terminal
afferent vascular twigs and extend into the periportal field from which these
twigs originate. Zones l', 2l, and 3' designate corresponding areas in a portiou
of an adjacent structural unit. In zones 1 and l', the afferent vascular twigs
empty into the sinusoids.
The circles A, B, and C delimit concentric bands of hepatic parenchyma arranged around a small portal field.
HEPATIC STRUCTURAL A N D P L 7 S C T I O S A I A I T S I T
17
Fig. 2 The vascular architecture of the liver in its relation to the hepatic
structural units. The longitudinal aspect of a smell portal space and its component structures is exposed. F o r simplification, only terminal portal venules
branching out from the portal vein in this space are drawn. The blood coming
up i n the portal and arterial vessels supplies the hepatic units of several hexagonal
fields. Xote the arcuate courses of these terminal vessels which follow the axes
of the irregularly arranged structural units. There are many anastomotic pathways permitting the flow of blood in all directions. LA = liepatic structural unit
penetrating a n hexagonal field which is situated well above the level of its origin.
PS = small portal space or canal. CV = central vein.
18
ItAPPAPORT, BOKOWY, L O C G H E E D A S D LOTTO
constitute the hepatic uiiits. The artei.ial twigs empty their
blood into the sinusoids situated in the inner third of the
structural unit. The cells adjacent to these sinusoids form
the core of the hepatic structural unit. They a r e the first to
be supplied with fresh blood (see fig. 1, zone 1). The cells
more rcmote from this site receive blood less rich in oxygen
and nutrients. It is important to note that although this
second area is almost midzonal (fig. 1, zone a), it does also
extend close to the portal fields. Finally, the zone of cells
situated farthest from the afferent arterial and portal twigs
extends not only to the pcricentral region but may also reach
the periportal areas. These areas viewed in the light of the
new concept would be considel-ed privileged by the circul a t’ion
and the cells farther from the portal triads as getting blood
of poorer quality. However from the study of our diagram
it becomes evident that all cells lying in the areas concentric
about the portal space do not share equally the possibility of
being supplied with fresh blood. Some cells in a r e a B or C
more remote from the portal field will have a n excellent blood
supply from the terminal vascular twigs branching out from
the samch portal space. Rut some cells in area A a r e supplied
with blood that comes from the distant end of the terminal
twig and, therefore, a r e a t a disadvantage with regard to
oxygen and nutrients.
Study of the pathology of an organ helps one to understand
the features of its normal structure. Thus, the analysis of
histopathological changes in a liver that has undergone ischemic necrosis after a n Eck fistula can serve a s a good
illustration of the circulatory pathways in the structural units
of the normal liver.
Figure 9 shows that in a liver suffering from ischemic
necrosis, islets of parenchyma have survived and extend symmetrically (a-a, b-b, c-c) around tei-niinal twigs branching
out from small portal fields. Some of these islands have the
same outline as zone 1 in figure 1.
The orientation of the lesions centc1.s around terminal
afferent vascular twigs, rather than aunnld the central
H E P A T I C S T K U C T U K A L -4KD F U N C T I O N A L IJTPTIT
19
veins to which the pathologists usually refer. The central
necrosis is often far from being “central” (fig. 9, X ) because
of the various degrees of anoxia in the periphery of d i f w e ? i t
adjacent structural units. I n cases where units adjacent to
the same terminal hepatic vein show a more or less identical
degree of necrosis a t their periphery (fig. 10, R, R ) , 3 the
terminal hepatic vein becomes the center of the necrotic
area. Here several adjacent berry-shaped units were damaged
equally by the anoxia. Their periphery was destroyed and
shrivelled. Consequently the necrosis has a regular pericentral
arrangement. It is not evident whether the band of neci-osis
as observed in figure ll-’is central, but everyone will see at
a glance the regular cuffs of surviving cells situated synimetrically around the afferent axial vessels of the liver units.
These rims of surviving tissue represent the barrier which,
because of better blood supply, has resisted the pathological
process, arid from here the regeneration will proceed. h
similar distribution of diseased and surviving liver tissue is
apparent in dietary cirrhosis in the rat as illustrated in figure 3 in Doctor H a r t ~ o f t ’ spaper which
I)ISCUSSION
Vuscular l a n d m z r k s : ( a ) central veisns. In the usual description of the hepatic hexagonal lobule stress was laid upon
the vascular architecture of the liver parenchyma, and its
exocrine activity was disregarded. Some authors even put
the emphasis on the endocrine activity of the liver (Maxiniow
and Bloom, ’48). However it remains obscure why drainage
of blood flow was considered so important and why an efferent
vessel was chosen as the dividing landmai-lr which should help
establish the smallest functional and structural unit in such
a complex parenchymatous organ.
3 F o r these slides the author is obliged to Captain R. Giges and associates of
the Army Medical Center in Washington, d i o repeated our experiments wit11
ischemia of the liver for the production of 1iep:itic conla.
‘See footnote 3.
See article by W. S. Hartroft in this issue.
20
RAPPAFORT, ROItOWY, LOTJGHEED A N D LOTTO
Analyzing the description of the venous drainage of the
Kiernan (1833) lobule, we find a peculiar anatomical arrangement deviating completely from the general principle of vascular anatomy. As a rule, the venous pathways predominatc
in number. I n the classical concept, as evidenced in a hexagonal field, 12 afferent ( 6 arterial, 6 portal) vessels are supposedly drained by one terminal vein. Either we must doubt
that the central veins arc1 in fact the smallest radicles of the
hepatic veins and state that the central veins result from
the confluence of smaller venules, or we must seek additional
ones draining the 6 pairs of afferent vessels. Several canals
of Deysach ('41) are of a size intermediate between siniisoids
and central veins; however their number is too small to fill
the gap in the vascular histology of the liver.
The axial vessels of the livei- unit which we described empty
their blood into a glomus of sinusoids which run, indeed,
toward a t least two terminal hepatic veins. However, thc
abrupt transition from small sinusoids into a large vein is
still unusual in vascular anatomy and quite unexplained. It
would make one suspect that the central vein is merely a
drainage center rather than the axis of a structural unit.
We are inclined to believe that the central veins may result
from the confluence of numerous small venules to which the
histologist might pay more attention in his descriptions.
( b ) Twminal afere9zt vascular twigs. The layout of 6
pairs of afferent terminal vascular twigs around and perpendicular to a central vein, into which all the sinusoids drain,
produces a hexagonal figure which is very pleasing to our
eye. This is one of the reasons why the hexagonal field was
taken as an indication for the existence of a three-dimensional
hexagonal lobule.
If we adopt vascular architecture as the principle for delimiting the smallest liver lobule, we should pay more attention to the observations on the hepatic circulation in vivo by
Knisely ('39), Wakim and Mann ( ' 3 2 ) and others. They
observed circulatory activity restricted to certain portions
of adjacent hexagonal fields while the sinusoids in the re-
HEPATIC STLt UC T CR AL A S I ) FCIVCTIOSSL C S I T
21
maiiiders of these fields stored blood. The flow of blood shifted
asynchronously from oiie group of sinusoids to another. We
believe that the active and resting sinusoids belong to different structural units. They became active or quiescent with
increases or decreases of blood flow in their axial vessels.
I n our description of the subdivision of the hexagoiial
vascular pattern into its components, attention was also
focussed on the terminal afferent vascular twigs. They mere
defined as the axes of the hepatic structural units which estend into adjacent sectors of neighboring hexagonal fields.
They accompany the bile ductules draining secretions from
the same area. Thus the trio of terminal channels fundamental to function and glandular structure form the basis
for defining the hepatic unit.
Irregularity of the heputic structural unit. The small parenchymal masses around the terminal vascular twigs and
bile ductules have by no nieans a rigid geometric arrangement
around the central veins. They may overlap each other by
differences in the individual growth processes. Their axial
vessels and bile ducts run in curved rather than in straight
lines. I n a microscopic field we see the trio of terminal
branches of portal vein, hepatic artery, and bile duct only a t
the points where they branch out from small portal spaces.
Here they are sectioned more o r less longitudinally. Rarely
a hexagonal field is completely outlined by straight lines of
terminal vascular branches or bile ducts cut longitudinally
in their entire length. Often microscopic fields around central
veins are not at all hexagonal, because no regular “interlobular” structures are seen. Instead of three portal triads,
with their outgrowing terminal branches, there are observed
transverse sections of small portal canals with their trios of
structures and sparse connective tissue. They represent the
axial vessels and bile ductules of units which by the growth
process of neighboring units may have been forced into courses
parallel, rather than their usual courses perpendicular to the
central veins. I n other fields, the greater number of portal
canals around a central vein can be interpreted as the result
22
RAPPAPORT, BOROTVY, LO U(+HEED .\ S D LOTTO
of twice sectioning the same arched " interlobular " structures.
However final answers to these questioiis can be given only
after a reinvestigatioii of the histology of the liver froni the
s u g g e s t d viewpoint, using irijectioii techniques and serial
sections, and coordinating the histological findings with microscopic observations in vii:o.
The i d r r w l trrchitectzil-r of thr hrpntic w i t s . Elias ('49a)
doubts the existence of liver cords because, in microscopic
sections, mainly unicellular, instead of the expected bicellular,
cords a r e seen between the sinusoids. The concept we put
forward might answer questions which led him to postulate
t h a t thc liver is composed of solid livcr plates with canals
for vessels and bile ducts.
If we assume that each structural unit is composed of many
tubular cords arranged perpendicularly to its axis, we might
compare each of these units to a spherical hrusli. Each bristle
would correspond to the caiialicular lumen of R bicellular
liver cord, and the cells of the cords would fill the spaces
between the bristles. B y fusion of the cords, liver plates
could be formed. They a r e traversed by the biliary capillary
network, emptying into the bile canaliculi, which in turn
converge upon the axial terminal bile ductule. Six of these
ber1.y-shaped parenchymal masses s u i ~ o u n dthe central vein
in oiic perpendicular plane. I n whatever plane a cut is made
through a hexagonal lobule, each of these spheroid structures
will be sliced iangentially. Thus, there will be few chances
of cutting marly of the bristles transversally and thereby
displaying bile canaliculi delimited by two liver cells. The
chances a r e greater for sectioning the liver cords tangentially
and finding shorter or longer unicellular chains interrupted
by adjacent sinusoids. This concept is in agreement with the
embryological development of the hunian liver from cords.
Relatiofi o f the hepotic zitzit to t h r hrxcigonzal patter9z. Tn its
original fetal aimmgement, the liver lobule may be coiiceived
of a s consisting of pareiichyinal cords forming tubular glands
around the terminal bile ducts. These tulmlar glands a r e surrounded by networks of sinusoids, into which arterial and
HEPATIC STRI-CTI‘RAL A A I ) FI‘NCTIOSAL V S I T
23
portal twigs empty their blood. The hexagonal pattern is
the result of a three-dimensional budding of the bile ducts
and an accumulation of fibrous tissue around them. This
developnient is exemplified in figure 8, where the three vertical
branches correspond to three bile ducts in three small neighboring portal spaces, and the stems of the leaves, to the
terminal branches of these bile ducts. The fibrous tissue surrounding them and the accompanying terminal vascular twigs
form the mcsenchynial cores of the structural hepatic units.
The lines that produce the hexagonal pattern indicate, in
fact, the axes of these units. The shape of the units growing
in a coilfined space is also determined by the growth of adjacent structures. Seithcr ideal, regular shape, nor complete
scparation from neighboring tissue and vascular and biliary
chaiinels can he expected. Interdependcnce is a basic principle of our oi*ganisrri.
Diferencrs bctwern, f l i e lwputic structurcil unit c m d other
concepts. Although in developing our coiiccpt we were stimulated by the work of Sabourin (1888), Mall ( ’06), Ayey ( ’32)
the hepatic structural unit that we present
and Opie (’M),
differs from the smallest liver units which they described.
Mall ( ’06) opposes to the hexagonal hepatic lobule a portal one,
defining the portal field as the center of the real lobule, Tn his
static description, he failed to correlate structure with function. However, in nen’er testboolis of histology, the “portal
unit ” 0 1 ’ “portal lohule” has been considered to he the “seeretory lol~ule.” 1 t is cyliiidi.ica1 in shapc. and its parenchyma
is arranged around the bile duct, hepatic a r t e r y and portal
w i n running in a portal space sheathed by fibrous tissue.
Hence, it has its spatial arrangement mainly parallel to the
central vein and the hexagonal lobule.
To correlate the structure and function of a gland n’c followed the iiatural courses of the terminal channels that supply
the niaterials necessary for function and those that carry
away the product of secretion. These channels a r e the terminal afferent vascular twigs and the bile ductules. Each of
these, when it first developed, subserved a definite amount
24
RAPPAPORT, BOKOWY, L O U G H E E D A X D LOTTO
of parenchyma, which we recognize as the anlage of the hepatic
structural unit. These units are grape-like, irregular agglomerations of hepatic parenchyma situated perpendicular
to the central veins and surrounding the terminal twigs of
the portal vein, hepatic artery and bile duct which branch
out from small portal spaces (see fig. 3 ) . Also, we consider
the parenchymal cells best supplied with fresh blood t o be
those adjacent to the terminal vasculai- twigs, even though
distant from the portal space (fig. 1).
Distribution of hepatic l e s i o m explained bg t h e coricept of
structural units. Once the hexagonal pattern of the liver
parenchyma is considered as resulting from the three-dimensional budding of terminal branches, the tissue that is contained in a hexagonal field ceases to be it uniform structural
mass. It is evident that lesions observed in one hexagonal
field do not necessarily belong to one structural unit. They
can be produced not only by pathological changes i n difierent
units whose axes lie in the same plane, but also by changes in
liepatic units which may originate above or below this plane
and extend into the same hexagonal field (fig. 2). This concept permits a rational approach to the thorny problem of
zonal necrosis. Focal and midzoiial necrosis observed in a
hexagonal field may be due to the tangential sectioning of a
necrotic area that belongs to the periphery of a structural
unit which lies above or below the plane of section. This
unit may have suffered from ischemia due to damage of its
afferent vessels.
Reference has been made to the difficulty in correlating the
distribution of necrotic lesions in experimental hepatic ischemia with the pathonomy that impaired circulation affects
the periphery, rather than the center, of a structural unit.
This inconsistency urged us to look for a better conformation
of structural and circulatory units. The lesions we observed
were more easily understood when we adopted the concept
of the structural hepatic unit. We found also that the terininal vascular branches growing out of a small portal field
offered clearer lines of orientation than the central veins
HEPATIC STRUCTVRAL A S D P U S C T I O N A L U N I T
25
which are buried in irregular masses of necrosis (fig. 9, X).
These necrotic areas are not only a t the circulatory periphery
of their own axial vessels, but also a t the periphery of those
supplying the neighboring units (fig. 1, zones 3-3’). It is
evident that circulatory disturbanccs due to the compression
of the sinusoids by the accumulated fat in the cells will show
up first in these peripliciral areas. Early cirrhosis following
such dietary fatty change replaces the destroyed cells with
fibrous tissue.G Thus the normal structure of the liver is
disclosed by fibrosis of the outskirts of the berry-like parenchymal units. These fibrous shells, containing shrivelled or
hypertrophied acinar-like structures, are barriers to the portal
circulation. They illustrate well the mechanism of the disturbance of the iiitrahepatic circulation which produces portal
hypertension by intrahepatic block.
SUMMAHY AND COIVCT>USIONS
1. A subdivision of hexagonal liver lobules into a structural
and functional unit has been postulated and supported.
2. The newly defined structural unit is a small, irregular,
berry-like, parenchymal mass situated around the trio of
terminal branches of portal vein, hepatic artery and bile duct,
growing out from a small portal triad and mainly running
perpendicularly to the central vein. The hepatic unit occupies
adjacent parts of neighboring hexagonal fields and extends
from the central vein of one hexagon t o the central vein of
another.
3. The axial vessels supplying the hepatic units empty
into a glomus of sinusoids woven around those liver cords
which are drained of their secretions by the terminal branch
of the bile duct that accompanies the axial vessels.
4. The liver cells situated close t o the afferent, terminal
portal and arterial twigs are the first to be supplied with
blood rich in oxygen and nutrients. The more distant the
hepatic cells are from the site where the terminal twigs empty
@Seefootnote 5, page 19.
26
RAPPAPORT, HOROWS’T, L O C G H E E D A S D LOTTO
into the siiiusoids, the poorer the quality of blood which
bathes them and the less their resistance to damage. This is
valid f o r the pericentral a s well as for the periportal parenchymal cells.
5. The presence of structural units in normal animal livers
x i s demonstrated hy siinultaiieous injection of two branches
of the portal vein, of the hepatic a r t e r y or of the bile duct,
with differently coloi~edgelatin masses of the same viscosity
under equal pressure.
6. The subdivision of the hcxagonal lobules into hepatic
units was shown to offer a better understanding of phpsiological and pathological processes in the liver.
’7. Ischemic necrosis of the liver, slight fatty change, and
eavly dietary ciri.hosis niakc the pattern of the structural
uiiits of the pareiiclipiiia apparciiit.
Tlie authors wish to express their thaiiks to Dr. C. €1. Rest
for his stiniulating iiitewst in this ~ o r k .They are grcatly
ohliged to Doctor Hartroft for his help and criticism. They
are grateful to llrs. Margaret Coniell for her valuable assistance in the prepai.ation of this papel., and to X s s E.
Blacltstock, to whom credit for the illustrations is due. ;\[any
thanlis go to W.D. TTilson for his technical assistance in the
preparation of the liver specimen.
LI TERA TURF: CITED
AREY, 1,. R. 1932 On the preseuce of the so-called portal lobulrs in the seal’s
liver. Anat. Rec., 51 : 315-32.
ELIAS,H. 1949a A re-exaiiiinntion of thc structure of t h e inainmalian Iil-er.
I. Parencliymal architectuw. Am. J . Anat., 84: 311-333.
1949b A re-examination of structure of inammalian liver ; hepatic
lobule and its relation t o vasculnr a n d biliary systems. Ibid., 85 :
3 79-486.
DFXS.\C€1, L. J . 1941 Tlie naturc a n d location of the “ sphincter-inerhanisiii”
in the liver a s determilied by drug actions a n d vascular injections.
Ani. J . Physiol., 13.3: 713-724.
KIFRSAS,F. 1833 The anatomy and physiology of the liver. Philos. Tr. Roy.
Soc. Loiid., 1?3: 711Li70.
H E P A T I C STRUCTURAL A N D F U N C T I O N A L U N I T
27
KNISELY,M. I€. 1949 Thc liver lobule. Liver Injury, Tr. 8th Conf. Josiah
Mac?.,Jr. Foiind:ition, New York., pp. 9-13.
____
1939 Microscopic observations of the circulatory conditions i n living
f r o g liver lobules. Anat. Rec., 7 3 : suppl., 269-270.
1952 Personal communication.
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MALL, F. P. 1906 A study of the structural unit of the liver. Am. J. Anat.,
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MAXIMOW,A. A., A N D W. BLOOM1948 Textbook of histology. W. B. Saunders,
Philadelphia, p. 420.
OPIE, E. I,. 1944 The pathogenesis of tumors of the livcr produced by butter
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SABOURIN,
C. 1888 Reeherchcs sur l’anatomie normale e t pathologique de la
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PLATE I
EXPLANATION OF FIGURE
3 Subdivision of the hexagonal lobules in hepatic structural units. The structural units (LA) are small berry-like parenchymal masses situated around the
trio of terminal branches of portal rein, hepatic artery and bile duct branching
out from a small portal space. L'A'= horizontal section through a red colored
hepatic unit, extending from oiie central vein to another.
28
H E P A T I C S T R U C T U R A L AND FUNCTIONAL U N I T
PLATE 1
RAPPAPORT, BOROWY, LOUGHEED AND LOTTO
29
PLATE 2
EXPLANATION OF FIGURES
4
Tissue block from the intermediate zone B = portal branch bringing i n black
gelatin mass. R = portal branch bringing in red gelatin mass.
5
Hepatic structural unit in the liver of a rabbit. The area clear of India ink
is centered around the trio of terminal branches of portal vein ( P V ) , hepatic
artery :ind bile duct. The latter is seen i n this section cut longitudinally. x 100
approx.
6
Hexagonal field broken down into differently cwlored sectors wliicli represeiit
parts of liver units iiijeeted through termiiial branches of the hepatic :irterg.
R = ayterial branch bringing in red gelatin mass. B = arterial branch bringiiig
in black gelatin mass. CV = central vein containing red and black color.
X 100 approx.
7
Dog’s liver injected througli the bile duct. The spread of the bluvk color
extends into sectors of adjacent hexagonal fields. Their central veins (CV)
are surrounded by red colored areas (here of gray color). x 100 appros.
30
HEPATIC STRUCTURAL AND FUXCTIONAL UNIT
RAPI’APORT, B O R O W Y , 1.OURHBED A S D L O T T O
31
PLATE 2
PLATE 3
EXPLANBTION O F FIGURES
8
Three ITertical branches, corresponding to threo bile ducts i n three neighboring small portal spaces, outline with the stems of their leaves an hexagonal field.
9
Isclieinic necrosis of a dog’s liver after Eck fistnla and ligation of the coinmon
hepatic artery. Rims of liver tissue have survived. They extend symmetrically
(a-a, 11-b, c-c) around terminal vascular branches. S = necrotic area, off-side
from central vein. X 60 approx.
10
Necrosis in a dog’s liver following experimental ischemia. The necrosis is
central, due t o the destruction of equally large peripheral parts of adjacent
structural units. Note the regular rims of surviving parenchyma (R) around
the axial vessels of the liver units. X 40 approx.
11 Ischemic necrosis in dog’s liver. The axial vessels of the hepatic structural
units are surrounded by equally wide cords of surviving cells. They enclose
band-like areas of necrosis in which central veins can hardly be identified.
X 150 approx.
32
HEPATIC
STRUCTURAL A m m x w n o N 2 u , UNIT
RAPPAFORT. BOHOWY, LOUGHEED A N D LOTTO
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33
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