THE HEALTHY LIVER MODULE 1

WebPath, Image
LIVER002

WHATS IN THIS MODULE?

Learning Objectives

Physiologic Functions

Blood Supply To and Through the Liver

The Microarchitecture of the Liver

Check Your Understanding:

Questions, Answers, Explanations
LEARNING OBJECTIVES:
1. Discuss the physiologic and immunologic functions of the healthy liver and its
cells, paying particular attention to the role of the liver in maintaining a healthy
immune system.
2. Outline blood flow to and through the liver.
3. Identify the following in a histologic image: central vein, portal triad, portal vein,
hepatic artery, bile duct, hepatocyte, Kupffer cell, sinusoid, and sinusoidal
endothelial cell.
4. Identify the following in an electron micrograph: hepatocyte, Kupffer cell,
hepatic stellate cell, space of Disse, and sinusoid.
5. Using examples, discuss the roles of pro- and anti-inflammatory cytokines in
maintaining a healthy liver.

LIVER FUNCTIONS
The healthy liver has over 500 functions, the main activities of which include:
metabolism, blood filtration, immune surveillance, and detoxification.

Approximately 1.6 liters of blood are filtered by the liver every minute! This enables the
near continuous breakdown and removal of wastes, drugs, and foreign substances
from the body. Specialized immune cells, including liver-specific macrophages called
Kupffer cells, assist in this process by trapping, phagocytosing, and eliminating
potential harmful substances entering the liver through portal circulation. These
substances include: gut-derived antigens, microbes and other pathogens, cellular
debris, endotoxins, and tumor cells that would otherwise cause inflammation or
infection.

In addition to filtration, the healthy liver plays a key role in maintaining glucose
homeostasis through its role in the uptake, transport, and release of glucose, which it
stores as glycogen. It also synthesizes, transports, and utilizes fatty acids and
deaminates proteins and amino acids. It stores fat-soluble vitamins (e.g. vitamins A, D,
E, and K) and certain minerals like iron and copper.

Hepatocytes, the parenchymal cells of the liver, express enzymes for detoxification.
The cytochrome P450 enzymes function to transform, degrade, or solubilize drugs and
toxins for excretion in the urine before reaching systemic circulation. Hepatocytes are
also responsible for secreting bile into bile ducts which empty into the duodenum of
the small intestine where they assist in digestion.

Furthermore, the liver supplies several important physiologic and immunologic

proteins to the blood, including albumin, lipoproteins, transferrin, coagulation factors
(e.g. fibrinogen and prothrombin), complement proteins, and acute phase proteins (e.g.
C-reactive protein and serum amyloid P).

Lastly, the liver maintains a constant size throughout life and is proportionate to the
size of the individual. Cells which are lost are replaced and tissue segments which
may become injured or removed can be regenerated.
BLOOD SUPPLY TO AND THROUGH THE LIVER
The liver receives a dual blood supply with 25% of the blood provided by the hepatic
artery and 75% provided by the portal vein. The hepatic artery carries oxygen-rich,
nutrient-poor blood. It originates as a branch of the celiac trunk off of the aorta. In
contrast, the portal vein carries partially oxygenated blood to the liver. It is enriched in
nutrients, bacterial products, toxins, and food antigens. The portal vein is a
component of the hepatic portal system; a series of veins which drain the capillary
beds of the stomach, spleen, small intestine, pancreas, and colon into the capillary
bed of the liver, to filter the blood. Blood from the hepatic artery and portal vein is
collected and emptied into the sinusoids where nutrients and wastes are filtered or
further metabolized by the liver. Blood then drains into the central vein (CV), which
merge to deliver blood to the right and left hepatic veins. Circulation is complete when
blood is emptied into the inferior vena cava (IVC), thereby constituting venous return
to the heart (Figure 1).

Figure 1: Hepatic Portal System

A schematic depiction of venous return from the gut and associated organs to the liver
(Note, the hepatic portal vein divides into right and left branches immediately before
reaching the liver (not shown here) and there is no portal artery!).

THE MICROARCHITECTURE OF THE LIVER

Hepatic arteries and portal veins are two components of the portal triad. As the name
implies, a portal triad contains three (3) different structures, all of which travel
together in a triad configuration. These include: a hepatic artery, a portal vein, and a
bile duct.

Sinusoids are vascular channels which carry blood from portal triads to the central
veins. Sinusoids are lined with a thin discontinuous endothelium and are located
between cords of hepatocytes. The discontinuous sinusoidal endothelium has a
discontinuous basal lamina that is absent over large areas. As mentioned previously,
central veins collect blood from the sinusoids and return it to the circulation.
 Figure 2: Portal Triads and Central Veins

A
A
CV
CV

Portal triads
Sinusoids

CV

http://hit-micrscopewb.hc.msu. edu/Virtual_MicroStatic /PSL-All.html Digestive System I Lab,

Integrative Question 4, Image 1 WED DS4

B The low-power image (A) and high-power image

(B) illustrate structures of the microarchitecture
Portal Triad
of the liver including sinusoids, portal triads and
central veins. The low-power images allow you to
Hepatic
see the relationship, in distance, between a
Artery
portal vein and central vein. The high-power
Portal Vein image allows you to see the structures found
within the portal triad. From your epithelium
histology lab you will note that both the portal
vein and the hepatic artery are lined by simple
Bile Duct squamous epithelium, however the bile duct is
lined by simple cuboidal epithelium. To further
distinguish the hepatic artery from the bile duct,
there is a thin wall of smooth muscle
surrounding the hepatic artery. Please note:
http://hit-micrscopewb.hc.msu.
edu/Virtual_MicroStatic /PSL-All.html
lymphatic vessels may also be present but are
VM WED-LH0139 usually difficult to see. CV= central vein
CELLS OF THE LIVER
The organization of the liver promotes the circulation of cells, proteins, and antigens.
In addition to providing structure to the organ, cells play vital roles in both physiologic
and immunologic functions. The cells in the liver which are critical to immune
protection are referred to as liver-specific immune cells and include: Kupffer cells,
dendritic cells (DCs), NK cells, NKT cells, B cells, and T cells. Antigen-rich blood from
the gut is confronted by these liver-specific immune cells which function to clear
pathogens, all the while averting infection, preventing inflammation and inhibiting
tissue damage. Additionally, hepatic stellate cells (HSCs), sinusoidal endothelial cells
(SECs), and hepatocytes also play important roles in maintaining the immune
protection of the liver.

Figure 3: Important Cells of the Liver

Sinusoidal

Lymph

Kupffer cell
Hepatocyte
Quiescent
B Hepatic
stellate
cell

Space of
Disse Sinusoidal
lumen

http://hit-micrscopewb.hc.msu. edu/Virtual_MicroStatic /PSL-All.html

Digestive System I Lab,Objective 5.1 Jastrow EMA-Leber4
The illustration (A) and electron micrograph (B) on the previous page, show some
important liver and immune cells along with their expected location in the liver. An
extracellular, extravascular region, called the space of Disse, is located between the
sinusoids and hepatocytes. The large fenestrations and absence of a basement
membrane facilitates exchange between hepatocytes and sinusoidal blood. In Figure
3A, HSCs are shown in two different shapes representing quiescent (left) and activated
(right) states. In the EM from Figure 3B, the quiescent HSCs can be identified by their
relatively large cytoplasmic lipid vacuoles containing vitamin A (one is outlined in
yellow). Kupffer cells, the resident macrophage of the liver is present in the lumen of
the sinusoid next to the electron dense RBCs. Hepatocytes (one is indicated by an
arrow) line the sinusoidal lumen on either side.
Hepatocytes
liver cells arranged in cords; comprise 70-80% of liver parenchyma
bordered by sinusoids but separated from sinusoidal lumen by space of Disse
responsible for glucose and fatty acid metabolism
participate in nutrient exchange with blood in sinusoids
excrete waste products and bile
produce complement proteins and acute phase proteins
participate in tolerance of bacterial products (e.g. endotoxin)

Kupffer Cells
resident macrophages of the liver; derived from monocytes
anchored to interior sinusoidal surface and exposed to blood from portal
circulation (Figures 3 and 4)
produce pro-inflammatory cytokines (e.g. IL-1, IL-6, TNF-) and chemokines
upon stimulation
express FcR, complement receptors, and pattern recognition receptors for
removal of circulating antigens (e.g. pathogens) by phagocytosis

Figure 4: Kupffer Cells in the Space of Disse

http://www.meddean.luc.edu/lumen/MedEd/orfpat http://hit-micrscopewb.hc.msu. edu/Virtual_MicroStatic /PSL-

h/images/kupffer.jpg All.html Digestive System I Lab, Self-study Review 4, WED
4_2_66
Kupffer cells can be seen in liver sinusoids using special dyes, which are phagocytosed
by these liver-specific macrophages. Kupffer cells are found at the tip of the arrows in
the Figure 4 images and can be differentiated from endothelial cells and hepatocytes.
Hepatocytes have circular, basophilic nuclei, whereas endothelial cells and Kupffer
cells have flattened nuclei.

Immune function of Kupffer cells: PAMPs, such as LPS produced by Gram-

negative bacteria, bind TLR4 on Kupffer cells and activate the cell. At low levels,
LPS stimulates Kupffer cells to produce the anti-inflammatory cytokine IL-10
whereas at high levels, they produce the pro-inflammatory cytokines IL-1, IL-6
and TNF-. Production of these cytokines induces hepatocytes to produce the
acute phase proteins, fibrinogen, and TGF-, all of which are indicators of
inflammation.

Hepatic Stellate Cells, HSCs (Figure 3)

extraluminal cells that reside in the space of Disse near sinusoids
store fat and 80% of the bodys vitamin A
produce reticular fibers (Type III collagen fibers)
may be activated and transformed into a myofibroblast-like cell (produces
Type I collagen)

Sinusoidal endothelial cells, SECs

endothelial cells which line sinusoids and act as a physical barrier to separate
blood from hepatocytes
maintain tolerance to antigens from gut microbiota
express adhesion molecules for leukocyte extravasation, MHC molecules and
costimulatory molecules for T cell activation

Immune function of SECs: MHC II is usually only expressed by SECs upon

exposure to high levels of extracellular antigen. SECs can produce the pro-
inflammatory cytokines IL-1 and IL-6 as well as activate leukocytes, such as T
cells, circulating through the liver using the two-signal hypothesis.

Hepatic Dendritic Cells

immature dendritic cells
reside in sinusoids and are in close contact with endothelium
highly phagocytic (express FcR, complement receptors) and migratory
(express chemokine receptors)
Peripheral leukocytes and liver-associated lymphocytes
These include B cells, T cells, monocytes, neutrophils, NK cells, and NKT cells. While
some cells are liver-associated and reside in the liver, others travel through the liver.
Together with endothelial cells, Kupffer cells, and dendritic cells, the leukocytes form a
strong innate immune defense system against circulating pathogens, tumor cells,
toxins, and cellular debris.

NK cells
comprise approximately 50% of innate lymphocytes in a healthy liver
two distinct populations provide immune protection against viruses, tumors,
and metastatic cells
detect changes that reflect altered self antigens using immune surveillance

Immune function of NK cells: These cells are activated using KARs which
recognize foreign antigens presented in MHC I molecules, whereas KIRs inhibit
NK cells that recognize self-antigen (Remember: many viruses downregulate MHC
I expression to evade the adaptive immune system fortunately, this lack of MHC
I/self-antigen expression results in NK cell activation). In addition, NK cells are
under the control of, and also produce, local cytokines to stimulate chemokine
production by hepatocytes which are necessary for leukocyte recruitment.

NKT cells
abundant in the liver; located in sinusoidal endothelium
unique; express both TCR and NK cell surface receptors
provide protection against intracellular bacteria, viruses, parasites, and
tumors
produce both pro- and anti-inflammatory cytokines

More information about cytokine function within the liver

Sinusoidal endothelial cells, Kupffer cells, and hepatocytes play a protective role by
producing a number of different cytokines. In the healthy liver, only minimal amounts
of cytokines are produced. However, in high concentrations, some cytokines such as
TNF- can result in hepatocyte damage. Thankfully, these damaging effects are
usually mitigated by the actions of TGF-.

IL-10 and TGF- (anti-inflammatory cytokines)

prevent liver injury
prevent activation of naive T cells
promote T cell differentiation into a regulatory T cell phenotype
inhibit maturation of dendritic cells in the liver

TNF- (pro-inflammatory cytokines)

prevent apoptosis of hepatocytes through the activation of NF-B pathway
promote hepatocyte regeneration and proliferation upon liver injury/damage
Practice Questions

1. An oral medication is prescribed to your patient to treat their bacterial infection.

You know this medication will be absorbed into the digestive tract and transported to
the liver. Based on your knowledge from this module, identify the correct flow of blood
through the liver given the options below.
A. inferior vena cava hepatic veins portal vein sinusoids central vein
B. hepatic artery portal vein sinusoid central vein hepatic vein
C. central vein sinusoid portal triad space of Disse bile duct
D. portal vein sinusoids central vein hepatic vein inferior vena cava
E. sinusoids space of Disse portal vein inferior vena cava hepatic artery

2. The purpose of routing the medication to the liver is to:

A. store the medication in hepatocytes to be released at a later time
B. solubilize the medication for excretion by the urinary system
C. be used as a building block for fatty acid synthesis
D. deaminate proteins such as acute phase proteins
E. be phagocytosed and degraded by Kupffer cells

3. Identify the structures labeled A, B, C, D and E in the histologic section below.

C
D

4. Identify the structures labeled A - E in the electron micrograph below.

D
E
A

B
5. The liver cell that is normally quiescent, stores most of the bodys vitamin A, and
has the capacity to become a myofibroblast when activated corresponds to which of
the following labeled cells in the same electron micrograph (above)?

6. From an immune perspective, a unique characteristic about the healthy liver is

(are):
A. Kupffer cells upregulate PRRs to maintain oral tolerance to pathogens
B. hepatic stellate cells provide the majority of immune protection
C. tight junctions of sinusoidal endothelium provide innate immunity
D. the majority of the liver parenchyma is comprised of NK cells
E. its ability to clear small amounts of circulating foreign material without
damage

7. Identify the correctly matched cell paired with its function.

Cell Function
A. NK cells produce anti-inflammatory cytokines
B. hepatocytes fatty acid metabolism
C. Kupffer cells store vitamin A
D. Hepatic stellate cell immune surveillance
E. Sinusoidal endothelial cell produce majority of bodys glucose

8. The cytokine which functions to indirectly prevent liver damage by promoting T cell
differentiation is:
A. IL-1
B. IL-6
C. TNF-
D. TGF-
Answers:

1. D
2. A. Portal Vein
B. Hepatic Artery
C. Bile Duct
D. Hepatocyte
E. Sinusoid

3. B
4. A. Kupffer cell
B. space of Disse
C. hepatic stellate cell
D. lymph
E. hepatocyte
5. C

6. E

7. B

8. D