Basic Sciences Organ Systems Gastrointestinal Hepatobiliary

Liver Anatomy and Physiology

Introduction
This lesson is a warmup to the hepatobiliary system, with an emphasis on hepatic. The bile duct does
contribute significantly to hepatic pathologies, but the gallbladder and biliary tree are a simple organ.
The gallbladder stores the bile the liver makes and secretes that bile into the duodenum when the
duodenum says so. The liver makes the bile in the first place (which is far more complicated than storing
it). The liver does a whole lot more than that, too.

There is no pathology in this lesson. This is about the liver anatomy, its vascular supply (including
the portal system), and the portal triad. Then we switch gears to histology, focusing on the sinusoidal
capillaries and the dual-direction function of the histological portal triads—blood in to the central
vein, bile out to the bile ducts. We then close with a brief discussion of each of the functions the liver
performs, with an overview of what could go wrong.

Liver Anatomy
The liver is a wedge-shaped organ located in the right upper quadrant. The liver is formed from a bud
of the foregut that makes the liver, gallbladder, and pancreas. It branches from the foregut into the
ventral (anterior) mesentery, the distal portions becoming the liver and gallbladder, and proximally,
forming the biliary ducts. Therefore, the liver is made from endoderm. Being derived from the foregut,
the liver, gallbladder, and pancreas are all fed by the celiac trunk. The liver develops in the ventral
mesentery, so it is encased in the peritoneum. The diaphragmatic surface of the liver (the top part) is
said to have a bare spot. The mesothelium lining of the liver pressed up against the mesothelium of the
diaphragm, thus fused, and the peritoneal cavity between the two structures was obliterated. Thus, the
bare spot is contiguous with the diaphragm—the adventitia of the liver connected to (and that must
be resected from) the adventitia of the diaphragm. The rest of the liver is in contact with the peritoneal
cavity, coated with mesothelium—the visceral peritoneum—except for where it gets its blood supply,
lymphatics, and nerves—the hepatoduodenal ligament (which is just mesentery).

The liver is just under the diaphragm on the right. It takes up a substantial portion of the abdominal cavity.

Figure 1.1: Liver Anatomy

This shows the mass of the liver in cross-section and in relation to the pancreas and stomach. This is a sagittal view showing
that the liver takes up the entire AP diameter. A coronal MRI of the liver showing its location under the diaphragm and over the
kidneys in the back.

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Gastrointestinal Hepatobiliary Liver Anatomy and Physiology

Liver Lobes and Vasculature

The liver is divided into two lobes—a smaller left lobe and a much larger right lobe—by the falciform
ligament. The liver can be subdivided further into eight surgical lobes. Each surgical lobe represents a
miniature version of the liver overall, containing a bile duct, hepatic artery, portal artery, and hepatic
vein. If a single surgical lobe is removed, it will not compromise any other surgical lobe. You can take
one of those lobes out of someone and put it into someone else. But we will not name them. We will not
even acknowledge them again. There are two lobes. Two. The functional left lobe is connected to the
left hepatic duct. All of the ductules and intrahepatic ducts from the left lobe will drain into the one
left hepatic duct. The functional right lobe is connected to the right hepatic duct. All of the ductules
and intrahepatic ducts from the right lobe will drain into the one right hepatic duct.

The liver has a dual blood supply. Both lobes are supplied by the portal vein and the hepatic artery. The
portal vein brings deoxygenated blood from all the veins of the GI tract in the abdominal compartment
(except for the inferior and middle rectal veins), bringing freshly absorbed nutrients (and potentially
toxins) to the liver for a first pass. The hepatic artery brings oxygenated blood and glucose to supply the
hepatocytes to do their work. The three hepatic veins drain the liver into the vena cava.

Figure 1.2: Liver Lobes and Vasculature

Surgically, the liver can be dissected into eight distinct lobules based on the vasculature and biliary drainage—one lobule can
be removed without compromising the remaining lobules. Physiologically, the liver is divided into two lobes, each draining into
a hepatic duct. And although there are three hepatic veins, the left and middle hepatic veins are so close together that they
act as one, causing the venous drainage to nearly mirror the biliary drainage—left and right liver lobes.

The common bile duct, hepatic artery, and portal vein together are called the portal triad. The bile ducts
carry bile away from the liver, whereas the hepatic artery and portal vein bring blood to the liver. And
even though they have fluid flowing in opposite directions, the portal triad is repeated again and again at
every level of the liver, right down to the hepatic lobules, the portal triad becoming numerous portal vein
venules, hepatic artery arterioles, and biliary ductules. Any smaller than that, and there are sinusoidal
capillaries (with mixed arterial and portal blood) flowing opposite to the bile ductules. And because
there must be flow in two directions, and blood flows from the portal triad (hepatic artery and portal
vein towards the central vein), there must be something else that carries bile away from the lobule to the
ducts. Those are bile canaliculi and will be discussed in the next lesson.

Canaliculi to ductules to ducts and out the liver. Portal vein to venules to sinusoids and the hepatic
artery to arterioles to sinusoids; sinusoids to hepatic vein venules to the hepatic vein out to the IVC.

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Gastrointestinal Hepatobiliary Liver Anatomy and Physiology

Liver Ligaments
The falciform ligament connects the liver to the anterior abdominal wall. Within the falciform ligament
is the remnant of the umbilical vein, the ligamentum teres. The falciform ligament is the remnant of the
ventral mesentery.

The hepatoduodenal ligament carries the portal triad—the hepatic artery, portal vein, and common bile
duct. It connects the liver to the upper third of the duodenum, where the biliary tree connects to the
duodenum via the pancreatic duct. The gastrohepatic ligament is the lesser omentum, connecting the
stomach to the liver and carrying the gastric blood vessels. Originally these two ligaments come from
the same ventral mesentery (the ventral mesentery behind/dorsal to the liver but anterior/ventral to the
stomach), but as the liver grows, the peritoneum-lined structure that carries blood vessels between the
liver and duodenum becomes a distinct peritoneum-lined structure that carries blood vessels between
the stomach and the liver.

Figure 1.3: Liver Ligaments

The liver develops in the ventral mesentery. The mesentery connects the developing liver to the abdominal wall, and it
connects the growing organs to each other. The mesentery will house the organs of the gut tube and the vasculature from the
aorta. The liver grows, expanding into the right side of the peritoneal cavity, and will grow so large that it nearly obliterates it.
The liver is connected to the stomach and duodenum by the remainder of the ventral mesentery, which becomes the lesser
omentum. In the lesser omentum is a hepatoduodenal ligament that carries the portal triad and the hepatogastric ligament,
which is the remainder of the lesser omentum.

The Lesser Sac

Almost the entire peritoneal cavity (not abdominal cavity, peritoneal) is the greater sac. There is that
one spot where a bunch of fusions happen and almost close off the lesser sac from the greater sac.
The lesser sac is the space behind the lesser omentum but in front of the parietal peritoneum (the
sheet of mesothelium lining the peritoneal cavity that abuts the connective tissue of the back of the
retroperitoneal organs). The ventral mesentery connects the gut tube to the ventral wall. The liver
grows in the ventral mesentery. The ventral mesentery from the liver to the wall becomes the falciform
ligament. The ventral mesentery from the liver to the duodenum and stomach is the lesser omentum
(technically the gastrohepatic ligament and duodenal hepatic ligament). The dorsal mesentery connects

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Gastrointestinal Hepatobiliary Liver Anatomy and Physiology

the spleen to the dorsal wall. The stomach is connected to the spleen through the splenogastric ligament.
The colon is attached to the posterior abdominal wall by mesocolon, the dorsal mesentery of the colon.
There is a fusion of the mesocolon and the greater omentum. The space that bounds the transverse
mesocolon, greater omentum, stomach, and lesser omentum is the lesser sac. This space has only one
entrance: the foramen of Winslow or the epiploic foramen.

Figure 1.4: Lesser Sac

The lesser sac is a space under the liver, behind the stomach, and in front of the kidneys. The sac is lined with omentum. Nothing
should ever be in that space. The rest of the peritoneal cavity is the greater sac. The lesser sac can be accessed by the foramen
of Winslow, which is found by retracting the liver and finding the hepatoduodenal ligament.

The lesser sac is formed by the fusion of the mesothelium. We are going to assume you know what
that means from the Abdominal Wall island. If you don’t, then here’s the thing that actually matters.
The clinical significance of this is that you are easily able to get your fingers (or a hemostat) around the
hepatoduodenal ligament (which is the entrance to the lesser sac), compressing the vessels contained
within (portal vein, hepatic artery) to stop bleeding during liver surgery. It’s also a problem area to wash
out if infected fluid gets in there, and it’s a place to lose a sponge if you’re a sloppy surgeon. Mostly, its
clinical use is hemostasis during liver surgery.

Liver Histology
The histological unit of the liver is a hexagonal-shaped liver lobule. The liver lobule is bound by a
fibrous band of connective tissue that separates it physically from the next lobule. In the middle of
a given lobule is a central vein that feeds into the hepatic vein. At each point on the hexagon is a
microscopic version of the portal triad—a branch of the bile duct, a branch of the portal vein, and a
branch of the hepatic artery. Blood comes in through the triads, mixing oxygenated and deoxygenated
blood, then flows in sinusoidal capillaries towards the middle, exiting through the central vein. The
central vein will eventually lead to a hepatic vein, and subsequently, the inferior vena cava. Bile flows
towards the portal triads on a separate network of ductules that carry only bile.

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Gastrointestinal Hepatobiliary Liver Anatomy and Physiology

Figure 1.5: The Liver Lobule

The liver is divided into microscopic, roughly hexagonal structures called liver lobules. At the corners of the hexagons are the
portal triads—portal vein, bile duct, and hepatic artery. At the center of the lobule is the central vein. Between the portal triad
and the central vein are sinusoids. Blood travels from the portal triad towards the central vein, and from the central vein out to
the hepatic vein and systemic circulation. Bile flows in the opposite direction through bile canaliculi out towards the gallbladder.

Hepatocytes are the main cells of the liver parenchyma. They are polyhedral. For convenience, and to
keep with the hexagonal theme, think of them as having six surfaces. Wherever two hepatocytes come
together is considered an apical surface. The apical (canalicular) surface houses the bile canaliculi, into
which hepatocytes secrete bile—bile acids, cholesterol, phospholipids, and bilirubin. Any free surface
in contact with a sinusoidal capillary is a lateral surface. Lateral (sinusoidal) surfaces have microvilli to
increase absorption from and secretion into the bloodstream. The hepatocytes don’t have a basement
membrane, they don’t have a basal layer, and therefore don’t have a basal domain. Instead, they maximize
their efficiency by having an “apical function” in every direction. Wherever there is another hepatocyte,
the “apical function” is bile. Wherever a hepatocyte meets a sinusoidal capillary, the ”apical function” is
everything else the hepatocytes do. All hepatocytes are exposed to at least two sinusoids at the same time.

Figure 1.6: Histological Liver

(a) Intermediate-magnification demonstrating a large portal triad (tract), likely with converging ductules and veins, which will
merge into a larger structure. Each portal triad (tract) consists of a bile duct (and often many smaller bile ductules), a hepatic
artery branch, and a portal vein branch. Lymphatic channels are also present. (b) Low-magnification micrograph of a normal
liver section showing several lobules. A hepatic lobule consists of a central vein (the circular white spaces in the middle of each
lobule), the hepatocytes surrounding the central vein, and the portal triads found within the connective tissue separates the
lobules. (c) High-magnification view of a normal liver section showing the central vein. It is surrounded by hepatocytes that are
arranged in two-cell-thick plates. The cords of hepatocytes are separated by cavernous fenestrated blood vessels—the hepatic
sinusoidal capillaries. The blood traverses from the portal triad to the central vein. Many red blood cells are visible in this slide.
(d) High-magnification view of a liver section showing cords of hepatocytes separated by hepatic sinusoids, which are filled
with red blood cells.

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Gastrointestinal Hepatobiliary Liver Anatomy and Physiology

The sinusoids are sinusoidal capillaries. These, like the bone marrow and spleen, have gaps in the
endothelium so large that entire cells can exit. The liver is a hematopoietic organ during embryogenesis,
so it had to be able to let immune cells into circulation. Being sinusoidal and having discontinuous
endothelial cells, the sinusoids also have a discontinuous basement membrane. The hepatocytes don’t
need a basement membrane. The endothelial cells do, so wherever there are endothelial cells, there is a
basement membrane. But wherever there isn’t a basement membrane, there is the free-flow exchange of
blood with hepatocytes. This is equivalent to massively increasing the radius of the capillary (remember
this when we get to portal hypertension; it won’t make sense now). This is also equivalent to allowing
whatever is in the blood onto the hepatocytes. That wouldn’t work well if any pathogen ever got into
the liver. So the endothelial cells work with resident macrophages, called Kupffer cells, in creating a
perisinusoidal space (eponym: space of Disse). The discontinuous collagen fibers of the discontinuous
basement membrane set a boundary. Within that boundary, hepatocytes have microvilli that massively
increase the absorptive and secretive surface area in the perisinusoidal space. In this sense, whatever
hepatocytes synthesize is immediately distributed into the bloodstream without any filtration. The
resident macrophages (Kupffer cells) share the lumen with the endothelial cells and reside on the
luminal side of the space of Disse. There, they are out of the way of hepatocytes’ work, but in the way of
invading pathogens. They occupy the larger gaps in the basement membrane, sampling for pathogens
and antigens.

Figure 1.7: The Hepatocyte

This is a busy but communicative illustration. First, sinusoids have large gaps in their lining. The endothelial cell and basement
membrane are periodically absent, enabling blood to reach the microvilli of the hepatocytes and giving the microvilli of the
hepatocytes access to the blood. Kupffer cells—resident macrophages—sometimes fill in for endothelial cells. The space
between what would be the intact capillary lumen and the hepatocytes is the space of Disse. Ito cells, dormant fibroblasts rich
with vitamin A, punctuate the hepatocyte epithelium. Hepatocytes hold on to one another but have no basement membrane.
Instead, both the “basal” and “apical” domains are specialized to absorb from the sinusoids and secrete into the sinusoids.
Separately, bile canaliculi are present between hepatocytes, into which those hepatocytes secrete bile.

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Gastrointestinal Hepatobiliary Liver Anatomy and Physiology

In addition are specialized cells known as stellate cells (also called Ito cells). They are periodically
seen nestled between two hepatocytes on the hepatocyte side of the perisinusoidal space, beneath the
discontinuous membrane and the protection of the resident macrophages. They store vitamin A. When
chronic inflammation occurs in the liver, these stellate cells lose their ability to store vitamin A and
differentiate into myofibroblasts that secrete collagen, resulting in the fibrosis characteristic of cirrhosis.

Figure 1.8: Electron Microscopy of Liver Sinusoids

(a) High-resolution electron micrograph of a Kupffer cell floating in the lumen (above) protecting the perisinusoidal space
(below) into which the darker grey hepatocytes are projecting their microvilli. (b) Zoomed out and stained for granules,
exocytosed vesicles (tiny grey round structures) are being released from two neighboring secretory hepatocytes, which are
full of black granules. Their apical projections are reaching into the perisinusoidal space, beneath two endothelial cells (that are
not touching) that line the fuzzy perisinusoidal space and the white sinusoid lumen. (c) With a low-power electron microscope,
we see hepatocytes (on the top and bottom of the image) with their apical projections in the perisinusoidal capillaries.
Spanning the width of the sinusoid are a large Ito cell (prominent nucleus, fat globules) and a Kupffer cell. This is an especially
neat shot because it shows a bend in the sinusoid. Between the Ito cell and the Kupffer cell are the apical projections of a
hepatocyte. The grey sausage-looking thing going up and right over the Ito cell’s upper left is the process of an endothelial
cell. The Kupffer cell is in the lumen, and the hepatocyte (coming out of the plane of the page at us) and its neighboring Ito
cell are within the perisinusoidal space.

Kupffer cells are macrophages. Stellate cells are fibroblasts. When things go wrong, they are the players
of acute inflammation that results in fibrosis. When things go well, stellate cells are a helpful source of
vitamin A for the body, and Kupffer cells keep the hepatocytes safe.

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Gastrointestinal Hepatobiliary Liver Anatomy and Physiology

Different Lobules for Different Folks

There are different ways to envision the liver. The classic lobule was described above, a liver lobule
defined by the histological boundary, the anatomical separation of hepatocytes using the connective
tissue that separates lobules from one another. There are two other ways a lobule can be defined: the
portal lobule and liver acinus.

The liver’s exocrine function is to secrete bile. If we draw imaginary lines between the central veins of
neighboring classic lobules, we create a triangular wedge. This area creates an arrangement similar to
that of other exocrine glands. The bile secreted by those hepatocytes ends up in the same bile duct. At
the center of this triangle is the portal triad, where the bile will eventually drain to. We’ll explain this
further when we talk about bile secretion in Hepatobiliary #2: Physiology of Bile and Bilirubin. This
triangular arrangement is the portal lobule.

The liver acinus is the structural unit that provides the best correlation between blood perfusion,
metabolic activity, and liver pathology. The hepatocytes of a classic lobule are connected to each other.
They are a physical unit. But hepatocytes in a lobule experience a different blood supply and so behave
differently based on their proximity to the portal triad. And the hepatocytes in one lobule that are as
close to the portal triad feel the same thing as the hepatocytes in another lobule that are that close to
the portal triad. Thus, the liver acinus is a function of proximity to the portal triad. There are three
functional zones of the liver acinus: periportal (zone 1), pericentral (zone 3), and the other one (zone 2).
Be careful as this is not an acinus—simple columnar cells that secrete into a common lumen—but rather
the name given to hepatocytes when considered in this physiological capacity (not our preference here at
OME, but something we don’t have a better alternative for).

Figure 1.9: Different Arrangements of the Liver Lobules

Anatomically, liver lobules are the way they are. Because there are portal venous drainage, hepatic artery irrigation, and
bile secretion, each lobule can be classified relative to the lobules around it. In the classic histological lobule, the lobules
are demarcated by the connective tissue visible on light microscopy. A portal lobule is in relation to the bile duct. The
hepatocytes closest to one bile duct will secrete bile that flows towards it. All hepatocytes secrete bile, but the triangle
formed by hepatocytes equidistant from one portal triad defines a portal lobule. Finally, arterial blood supply defines a portal
acinus lobule. Oxygenated blood flows in through the portal triad’s branch of the hepatic artery. It fills the fibromuscular
stroma between two triads. It then flows through sinusoids towards the central vein. As it passes through sinusoids, the first
hepatocytes to encounter the blood consume oxygen and glucose, such that the hepatocytes nearest the central vein will
receive the least oxygen and glucose from the blood. We’ll explain zones in detail below.

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Gastrointestinal Hepatobiliary Liver Anatomy and Physiology

Zone 1 is termed periportal and is nearest to the portal triad. It is the periphery of the classic lobule.
It receives the highest dose of oxygen and glucose, taking both from the blood as it courses down the
sinusoids. It is the last to suffer ischemic insult and the first to regenerate after ischemic insult. This zone
also receives the highest dose of toxin; therefore, it is the most susceptible to toxins. This is the first zone
to show injury from biliary duct obstruction. Periportal hepatocytes, receiving the most oxygen and
glucose, specialize in oxidative metabolism.

Zone 3 is termed pericentral. It is the farthest from the biliary tree and closest to the central vein. It
is the center of the classic lobule. It gets the lowest dose of everything. It is the last zone to be given
oxygen and glucose. Zone 1 takes all the resources before they get to zone 3. But zone 1 also takes the
brunt of the toxic exposure before it gets to zone 3. Zone 3 is the first to show fat accumulation, called
steatosis (see Hepatobiliary #4: Metabolic Liver Disease). Zone 3 feels the pressure of backup, similar to
zone 1. The pressure they feel is exerted by the portal vein. This is the first area to suffer in congestive
hepatopathy. Pericentral hepatocytes specialize in detoxification of drugs and lipid synthesis.

Zone 2 is in the middle and shows graduation from 1 to 3, those hepatocytes closer to zone 1 act more
like hepatocytes of zone 1. Those hepatocytes closer to zone 3 act more like hepatocytes of zone 3. Zone
2 is never the right answer on a licensing exam because it is neither periportal nor pericentral.

Every hepatocyte has the ability to do all the functions of the liver. The metabolic activity of any one
hepatocyte is determined by the microcirculation in which the hepatocyte exists. If the flow of blood
is experimentally reversed, such that zone 3 cells get the first take at the nutrients, they become like
hepatocytes of zone 1, and the hepatocytes that were zone 1 behave like zone 3. It is, therefore, not their
physical location but the changes in the microcirculation that direct hepatocyte function.

The portal canals are the fibrous septae that separate classic lobules. Blood flows easily through these
canals, so the distribution of oxygen and glucose is considered to be in an ellipsoid shape around the
canals, as shown in Figure 1.9.

Figure 1.10: The Zones of the Liver Acinus

The distance from the portal canal and the blood vessels that feed the sinusoids define different zones. Zones change the
function of the hepatocyte by delivering a varying microcirculation concentration. Histological assessment showing the change
in appearance to match the change in behavior.

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Gastrointestinal Hepatobiliary Liver Anatomy and Physiology

Why Zones Matter

The liver is responsible for the biotransformation (“make more water-soluble”) of endogenous
compounds (steroids and bilirubin) and exogenous substances (drugs and toxins). Pericentral
hepatocytes (zone 3) tend to detoxify drugs. Biotransformation happens in two nonlinear phases. Phase
1 is irreversible and tends to break molecules up, exposing a single polar group. Phase 2 is reversible
and tends to use that polar group to make a conjugate of the molecule, substantially increasing its water
solubility. This was the subject of General Pharmacology #4: Metabolism/Biotransformation. Phase 3—
hepatocytes secreting the products of phase 1 and phase 2 metabolism either into the blood or bile—was
not covered in that lesson. The generalities of phase 3 are not covered anywhere in this course.

Because of its vascularity, sinusoids, and Kupffer cells, the liver acts as an important filtering mechanism.
The macrophages clear the blood of old and dying red blood cells, endotoxins, and circulating organisms.

Figure 1.11: Why Zones Matter

(a) Low-powered magnification showing normal hepatocytes around the central vein, but steatosis (white) surrounding
a portal triad, and early fibrosis at the triad. (b) High-powered magnification that reinforces panel a—periportal steatosis,
pericellular fibrosis (green), and normal hepatocytes near the central vein. (c) In contrast, this moderate-powered
magnification demonstrates steatosis and pericellular fibrosis near the central vein. This is pericentral steatofibrosis.

Citation
Figure 1.1: Courtesy of Radiopaedia.

Figures 1.6, 1.10c, 1.11c: Courtesy of WebPathology.

Figure 1.8: © H. Jastrow www.drjastrow.de licensed to OnlineMedEd.

Figure 1.11: by Nephron, licensed under CC-BY-SA-3.0.

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