++
At the 18th day of gestation (2.5-mm stage), a thickening of
the ventral floor of the distal foregut, corresponding to the future
duodenum, heralds the appearance of the hepatic diverticulum. This
diverticulum is formed from the proliferation of endodermal cells
at the cranioventral junction of the yolk sac and foregut. Subsequently,
the hepatic diverticulum penetrates the adjacent mesoderm and capillary
plexus, known as the septum transversum. Cellular interactions between
the endoderm and mesoderm result in rapid cell proliferation and
the formation of hepatocytes, angioblasts, and sinusoids.1
++
By the third and fourth weeks of gestation (3- to 4-mm stage),
the growing diverticulum enlarges to form a double diverticulum
that projects into the septum transversum, then divides into a solid
cranial portion and hollow caudal portion is evident by the 5-mm stage.
The cranial portion differentiates into proliferating cords of hepatocytes
and intrahepatic bile ducts while the smaller caudal portion (pars
cystica) forms the primordium of the gallbladder, common bile duct,
and cystic duct.
++
The budding liver sequentially invades the vitelline veins and
then the umbilical (placental) veins. The vitelline veins run from
the gut–yolk sac complex to the heart. As the liver invades
the vitelline veins, the midsection of the veins becomes capillarized.
The caudal ends persist as the primitive portal veins, and the cranial
ends as the primitive hepatic veins. During the 6- to 7-mm stage
part of the left umbilical vein becomes the ductus venosus, which
shunts placenta derived arterial blood from the umbilical vein to
the inferior vena cava. After birth the obliterated prehepatic segments
of the umbilical veins atrophy to become the round ligament and
the ductus venosus becomes the ligamentum venosum.
++
The hepatocytes of the hepatic portion grow as thick epithelial
sheets intermingling between branching channels of the vitelline veins
within the septum transversum to form a system of connecting liver
cell plates, and the capillaries become the hepatic sinusoids. The
sinusoids, present by 5 weeks of gestation, act as templates for
the three-dimensional growth of the hepatic cords. The liver cell
plates are initially 3 to 5 cells thick. However, over time they
gradually transform to one-cell-thick plates, a process that is
not complete until 5 years of age. Intrahepatic bile ducts begin
to form at 6 weeks of gestation within the hilum of the liver and
gradually spread to the periphery until complete at 3 months.
++
The pars cystica is initially hollow, but epithelial proliferation
obliterates the lumen early in its development. Therefore, both
the primitive gallbladder and common bile duct consist of solid
chords of epithelial cells directly beneath the developing liver
in the 6- to 7-mm embryo. Recanalization of the common bile duct
and hepatic duct occurs in the 7- to 8-mm and 10-mm embryo, respectively.
At the 16-mm stage the proximal gallbladder and cystic duct are
hollow. At the third month the gallbladder is fully hollow, and
the intrahepatic and extrahepatic biliary structures are joined.
Bile secretion into the duodenum starts by the fourth month.
++
In the third month the liver begins to store iron, and hematopoietic
elements derived from the mesenchyme of the septum transversum localize
to the extravascular component of the lobule. The liver thus becomes
the major blood-forming organ of the embryo. This function is gradually
transferred to the developing bone marrow so that by birth only
an occasional focus of hematopoiesis remains in the liver.
+++
Macroscopic Structure
++
The adult liver weighs 1200 to 1500 g, representing 2% of
the total adult body weight. In neonates and young infants the liver
is proportionally even larger, accounting for 5% of the
total body weight. The liver rests below the diaphragm, rising to
the level of the nipple at the fifth intercostal space with its
distal edge at or above the right costal margin. It is held in place
by the falciform and triangular ligaments. During fetal life the
falciform ligament conducts the umbilical vein from the umbilicus to
the liver. After birth this vein atrophies to form the ligamentum
teres. A thin, firm, and smooth capsule (Glissen capsule) covers
the liver and is continuous with the porta hepatis where the portal
vein, hepatic artery, and common bile duct enter the liver.
++
At the porta hepatis, the right and left hepatic ducts coalesce
to form a common hepatic duct located to the right of the main hepatic
artery, in front of the portal vein. The common hepatic duct is
joined by the cystic duct, which drains the gallbladder at its right
side to create the common bile duct. The common bile duct joins
the pancreatic duct in 85% to 90% of the cases
just proximal to the ampulla of Vater, which empties into the duodenum. Anatomic
variants include a longer common channel that has been associated
with choledochal cysts, pancreatitis, and gallbladder carcinoma,
or a separation of the pancreatic and common bile ducts such that
they drain separately. The ampulla of Vater is encased by the sphincter
of Oddi, a complex of smooth muscle fibers that regulates the flow
of bile into the intestine.
++
The liver has a dual blood supply. The portal vein, which is
rich in nutrients as it drains the gastrointestinal tract and splenic
vascular beds, carries approximately 75% of the blood to
the liver. The hepatic artery, rich in highly oxygenated blood,
usually arises from the second branch of the celiac artery, although this
is variable. In 20% of cases the right hepatic artery arises
from the superior mesenteric artery rather than branching off of
the common hepatic artery. The hepatic veins that drain the liver
into the suprahepatic inferior vena cava are formed by the union
of the central veins.
++
Several approaches are used to demarcate sections of the liver.
Traditional anatomic descriptors divide the liver into lobes including
the right, left, quadrate, and caudate lobes. The Reidel lobe is
a downward tongue-like projection of the right lobe. The left lobe
is separated from the right by the attachment of the falciform ligament,
the umbilical fissure, and the attachment of the ligamentum venosum.
The caudate lobe is demarcated by the attachment of the lesser omentum
and the porta hepatis anteriorly, the ligamentum venosum on the
left and anteriorly, and the vena cava posteriorly. The right side
of the caudate lobe tails out to attach to the right lobe and is called
the caudate process. The quadrate lobe is defined as the bulge defined
by four borders: the gallbladder and umbilical fissure, the liver
edge anteriorly, and the left side of the hepatic hilum posteriorly. Another
approach is to divide the liver into functional sections based upon
vascular supply rather than gross anatomy. A vascular watershed
intersects the gallbladder fossa and the vena cava fossa, dividing
the liver into nearly equal halves (the right side representing
60% of the liver volume).
++
A universal terminology has now been adopted that combines both approaches
as shown in eFigure 418.1.2 The
liver is divided into hemilivers along the plane that intersects the
gallbladder fossa and the fossa for the inferior vena cava (the
midplane of the liver). Further divisions of the liver into segments
are based on the internal anatomy of the hepatic artery and bile
duct so that the left hemiliver contains segments 2 through 4 and
the right hemiliver contains segments 5 through 8. The caudate lobe
is composed of segments 1 and 9. This segmentation schema is clinically
relevant in the context of pediatric liver transplantation, allowing
transplantation of a left lateral section.
++
+++
Microscopic
Structure
++
The microscopic anatomy of the liver had traditionally been defined
as lobules with a portal tract (bile duct, branches of the hepatic artery
and portal vein, along with nerves and lymphatics) and central vein.
The edges of liver cells that encircle each portal tract form the limiting
plate. However, in vivo microcirculatory studies revealed that the
functional unit of the liver is the acinus (Fig.
418-1). This
is based on the fact that the most oxygenated and nutrient-rich blood
is in the portal and periportal areas, whereas the least oxygenated
blood is centrilobular. The central vein is designated as the terminal
hepatic venule, the portal area zone 1, and the hepatocytes around
the terminal hepatic venule zone 3. The acinus is composed of hepatocytes
arranged in plates of cells with bile canaliculi between them along
with sinusoids on the vascular sides. Zone 1 cells form the most
active core of the acinus and are the last to die and the first to
regenerate. Zone 3 cells are the most prone to toxic, viral, or
anoxic injury.
++
++
Hepatocytes represent 60% of the liver cell population
and 80% of the cell volume. The organelle content within
the hepatocyte varies with location in the acinar zone. Those in
zone 1 are oval and oblong and have more mitochondria, whereas the
zone 3 hepatocytes are round and have fewer mitochondria. Mitochondria
account for 17% of the cell volume and are the most numerous
of the organelles, with about 2200 per hepatocyte. Peroxisomes are
1% to 2% of the hepatocyte volume and are vital
in hydrogen peroxide metabolism. They are more numerous in zone
3 and play an important role in oxidation of fatty acids and detoxification.
Lysosomes are electron-dense cytoplasmic organelles responsible
for degrading biological material using acid hydrolases. The endoplasmic
reticulum constitutes 19% of the cell volume and is the
site of protein synthesis. The Golgi apparatus is responsible for
processing of macromolecules.
++
The functions of the hepatic sinusoid lining cells include pinocytosis, phagocytosis, erythrophagocytosis,
iron metabolism, clearance of immune complexes and antigens, and
secretion of endogenous pyrogens, collagenase, lysosomal hydrolases,
and erythropoietin.3 The arrangement of these sinusoid-lining
cells has been clarified through the use of scanning electron microscopy
and rapid freeze fixation. The endothelial cells form the wall of
the sinusoid, separating the sinusoidal lumen from the subendothelial
space of Disse. The sinusoidal endothelial cells lack a basement
membrane and are perforated by abundant small fenestrae (average
diameter 100 nm) in clusters called sieve plates, which act as blood-hepatocyte barriers. These
fenestrae are denser in zone 3 than zone 1 and change in response
to hormones, anoxia, injury, and drugs. Microvilli of the hepatocytes
protrude into the sinusoid through the fenestrae. The endothelial
cells also express Fc receptors, suggesting a role in removing immune
complexes. The space of Disse is located between the endothelial
lining and the hepatocyte. As large blood cells move through the
small sinusoids, they push the endothelium closer to the hepatocyte,
thus promoting the circulation of plasma along the space of Disse.
Lymph flow extends from the space of Disse to portal lymphatic vessels
at the hilum of the liver.
++
Kupffer cells are hepatic macrophages most abundant in zone 1
within the sinusoidal wall, anchored to endothelial cells. These
cells endocytose and destroy microorganisms, clear endotoxins and
senescent erythrocytes, and can act as antigen-presenting cells.
When activated they release IL-1, IL-6, TNFα, TGF-β,
LTB4, and interferon. Stellate cells (formerly called Ito
cells) are located in the space of Disse and are fat-storing cells.
They store vitamin A, participate in retinoid metabolism, produce
extracellular matrix proteins such as collagen I, III, IV, V, and
VI, laminin, fibronectin, and proteoglycans and are thus responsible
for hepatic fibrosis seen with chronic injury. Pit cells are large,
granular lymphocytes attached to the sinusoidal wall that have natural
killer activity. They are extrahepatic in origin and have a role
in immune surveillance and hepatic antitumor defense.
++
Biliary drainage begins by secretion of fluid into the small
biliary canaliculi formed by specialized membranes of adjacent hepatocytes. These
small biliary canaliculi form channels continuous with the short
duct of Hering that join the cholangioles at the limiting plate
of the portal areas. These cholangioles then merge into larger bile
ducts.