PHYSIOLOGY AND PATHOPHYSIOLOGY OF LIVER

JOURNAL OF PHYSIOLOGY AND PHARMACOLOGY 2008, 59, Suppl 1, 107–117
www.jpp.krakow.pl
G. RAMADORI, F. MORICONI, I. MALIK, J. DUDAS
PHYSIOLOGY AND PATHOPHYSIOLOGY OF LIVER
INFLAMMATION, DAMAGE AND REPAIR
Department of Internal Medicine, Section of Gastroenterology and Endocrinology,
Georg-August-University Goettingen, Goettingen, Germany
The liver is the largest organ of the body. It is located between the portal and the
general circulation, between the organs of the gastrointestinal tract and the heart. The
main function of the liver is to take up nutrients, to store them, and to provide
nutrients to the other organs. At the same time has the liver to take up potentially
damaging substances like bacterial products or drugs delivered by the portal blood or
microorganisms, which reach the circulation.
The liver is not only an important power and sewage treatment plant of the body. In
fact, the liver is probably the best example for a cheap recycling system. Both
parenchymal and nonparenchymal liver cells participate in the clearance activities.
The function of the liver as clearance organ, however, harbors the danger that the
substances that should be degraded and/or eliminated lead to tissue damage. Thus,
effective defense mechanisms are necessary. Among the nonparenchymal cells
Kupffer cells, sinusoidal endothelial cells, and natural killer (NK) lymphocytes exert
cellular defense functions for the whole body but also for the liver itself.
Furthermore, each cell type of the liver, including the hepatocytes, possesses its own
defense apparatus.
K e y w o r d s : liver; inflammation
LIVER INFAMMATION AND INJURY - BASICS AND ASPECTS
The classical picture of acute inflammation and damage in the liver is the
acute hepatitis caused by different noxae. It is thought that inflammation not only
precedes but is also needed to generate damage of "stressed" hepatocytes.
Hepatic fibrosis is the common endpoint for most types of chronic liver injury. It
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was considered to be an irreversible process, especially when the complete
picture of cirrhosis is present.
When damage is followed by elimination of cellular debris and of the
"stressing" agents regeneration and restitution of integrity are the terminal
consequences. When elimination of the agent is not possible inflammation and
fibrosis follow.
Different types of disease may lead to different patterns of fibrosis during
disease progression (1, 2). Different fibrogenic cells may predominate in different
types of fibrosis.
The classic forms of acute viral hepatitis are followed by complete recovery
of the liver. The hallmarks of chronic infection, caused by infection with
hepatotropic viruses (hepatitis C and hepatitis B virus) are inflammation, the
death of hepatocytes and finally liver fibrosis (3).
Alcoholic hepatitis (due to alcohol abuse) and non-alcoholic steatohepatitis
(caused by insulin resistance and obesity, diabetes mellitus, and/or
hypertriglyceridemia, etc.) are associated with a change in hepatocyte lipids on
histology, hepatocyte ballooning/necrosis, neutrophil infiltration and the
development of a particular type of fibrosis.
Obstruction of the biliary tree for several weeks to months, leads to hepatocyte
necrosis and to lobular bile infarcts. A ductular reaction develops at the periphery
of the portal tracts, extending towards the neighbouring portal tracts and into the
parenchyma. In this case an extensive proliferation of periductular
(myo)fibroblasts can be observed (4).
CELLS IN LIVER INFLAMMATION
Hepatocytes make up 70-80% of the cytoplasmic mass of the liver. These cells
are involved in protein synthesis, protein storage and transformation of
carbohydrates, synthesis of cholesterol, bile salts and phospholipids, and
detoxification, modification and excretion of exogenous and endogenous
substances. The hepatocyte also initiates the formation and secretion of bile.
Hepatocytes display an eosinophilic cytoplasm, reflecting numerous
mitochondria, and basophilic stippling due to large amounts of rough
endoplasmic reticulum and free ribosomes. The average life span of the
hepatocyte is 5 months; they are able to regenerate. Hepatocytes are organised
into plates separated by vascular channels (sinusoids) (5). The hepatocyte plates
are one cell thick in adult mammals. Hepatocytes are able to synthesize
hormones, like insulin-like-growth-factor IGF-1 (6), thrombopoietin (7), and also
erythropoietin (8). They also synthesize cytokines like interleukin (IL)-8 (9) and
respond to acute phase mediators like IL-6, with the synthesis of acute phase
proteins like C-reactive protein (CRP) (10) or serum amyloid A (SAA) (11) and
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many others. The cells possess different intracellular defense proteins like hemeoxygenase-1 (HO-1) (12).
When however the defense mechanisms are not sufficient to withstand the
damaging attacks cells start to synthesize chemokines (CXC-chemokines like:
monokine-induced by gamma interferon (MIG) (13), gamma-interferon-inducible
protein (IP-10) (13), cytokine-induced neutrophil chemoattractant (KC) and
macrophage inflammatory proteins (MIPs) (MIP-1, MIP-2, MIP-3) (14), which
are supposed to be responsible for attraction of inflammatory cells like
granulocytes and mononuclear phagocytes and to activation of resident
macrophages (Table 1, Fig. 1). In the attempt to eliminate the damaging noxae the
defense response however leads to death of the stressed hepatocyte.
Hepatic stellate cells (HSC) (and liver (myo)fibroblasts) have modulatory
roles in inflammatory conditions, based on their capability of cytokine and
chemokine production. The quiescent Stellate (Ito) cells (HSC) store vitamin A,
but produce extracellular matrix and collagen when activated. They are located in
the space of Disse between hepatocytes and endothelial cells (1,2,5,15).
Hepatic stellate cells might also play a role during liver inflammation. ICAM-1
and VCAM-1 expression was present in HSC in vitro and in cells located in the
sinusoidal/perisinusoidal area of normal liver. Growth factors, e.g., transforming
growth factor-β1, down-regulated ICAM-1- and VCAM-1-coding mRNAs and
stimulated N-CAM expression of HSC. In contrast, inflammatory cytokines like
tumor necrosis factor-alpha reduced N-CAM-coding mRNAs, whereas induced of
ICAM-1- and VCAM-1-specific transcripts by several fold. HSC might be important
during the onset of hepatic tissue injury by modulating the recruitment and migration
of mononuclear cells within the perisinusoidal space of diseased livers (16).
In addition, the secretion of several cytokines and chemokines was
demonstrated in hepatic stellate cells including MCP-1, RANTES, IL-8 (17-19)
(Table 1, Fig. 1).
Sinusoids display a discontinuous, fenestrated endothelial cell lining. The
sinusoidal "wall" does not possess a basement membrane and the endothelial cells
are separated from the hepatocytes by the space of Disse which drains lymph into
the portal tract lymphatics (5). Under normal conditions the hepatic sinusoidal
endothelial cells express low levels of Rantes, macrophage-chemotactic-protein1 (MCP-1), IL-8 and MIP-1α. These factors are involved in the routine leukocyte
Table 1. Induction of chemical mediators in liver cells populations during liver inflammation
Liver cells
Mediators
Hepatocytes
Sinusoidal Endothelial Cells
IL-8, IP-10, MIG, MIP-1, MIP-2, MIP-3, KC
RANTES, MCP-1, IL-8, MIP-1α, MIP-1β;
MIG, ITAC
IL-1, IL-6, IL-10, IL-18, TNF-α, TGF-β,
MIPs, IL-8, IP-109, KC/GRO, RANTES
IL8, RANTES, MCP-1
Kupffer Cells
Hepatic Stellate Cells
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A: Sinusoidal structure in normal liver
B: Changes in liver inflammation
Fig. 1. Scheme of sinusoidal structure in normal liver (A) and in liver inflammation (B). The
hepatocellular stress induced by hepatotoxins, or by viruses, may lead to activation of liver resident
macrophages on one side and to the release of chemokines on the other side. Proinflammatory
cytokines are released by natural killer cells as well as by Kupffer cells. They induce an increased
expression of cell adhesion molecules like intercellular cell adhesion molecule-1 (ICAM-1) and
vascular cell adhesion molecule-1 (VCAM-1) on the portal and/or sinusoidal endothelial cells and a
downregulation of platelet endothelial cell adhesion molecule (PECAM-1). These molecules allow the
recruitment and sinusoidal transmigration of inflammatory cells toward their target, the hepatocyte.
111
recirculation and immunological surveillance. During inflammation the
chemokine expression profile of the normal hepatic endothelium changes. These
changes are characterized by expression of high levels of MIP-1β, IP-10, MIG
and IFN-gamma-inducible T cell alpha chemoattractant (ITAC) (Table 1, Fig. 1).
Similarly to the chemokine profile the expression pattern of adhesion molecules
also changes in the endothelial cells (20). Under normal conditions the hepatic
sinusoidal endothelial cells express platelet endothelial cell adhesion molecule-1
(PECAM-1), vascular adhesion protein-1 (VAP-1) and intercellular cell adhesion
molecule-2 (ICAM-2). During inflammation this expression pattern changes,
characterized by the downregulation of PECAM-1, and upregulation of ICAM-1,
of vascular cell adhesion molecule VCAM-1, and of P and E selectins (20).
Kupffer cells are scattered within the liver sinusoid, they are the major part of
the reticuloendothelial system and phagocytose spent erythrocytes. Kupffer cells
are the specialized macrophages of the liver that form the major part of the
reticuloendothelial system (mononuclear phagocyte system). The cells were first
observed by Karl Wilhelm von Kupffer in 1876 (21). In 1898, after several years
of research, Tadeusz Browicz, a polish scientist, identified them correctly as
macrophages (22-23).
Their development begins in the bone marrow with the genesis of
promonocytes and monoblasts into monocytes and then on to peripheral blood
monocytes completing their differentiation into Kupffer cells (24).
The red blood cell is broken down by phagocytic action and the hemoglobin
molecule is split. The globin chains are reutilized while the iron containing portion
or heme is further broken down into iron which is reutilized and bilirubin, which
is conjugated with glucuronic acid within hepatocytes and secreted into the bile.
Helmy et al. (25) identified a receptor present in Kupffer cells, the
complement receptor of the immunoglobulin family (CRIg). Mice without CRIg
could not clear complement system-coated pathogens. CRIg is conserved in mice
and humans and is a critical component of the innate immune system (25).
During liver injury induced by hepatotoxins or by Gram-negative bacterial
lipopolysaccharide (LPS), or in association with sensitizers such as Dgalactosamine, CCl4, dimethylnitrosamine, acetaminophene, alcohol, etc. the
Kupffer cells get activated. Activation of Kupffer cells results in secretion of a large
number of chemical mediators (cytokines: IL-1, IL-6, IL-8, TNF-α, etc. chemokines:
C-X-C chemokines: MIP-2, IP-109, KC/GRO; C-C chemokines: MIP-1α, MCP-1,
RANTES), most of which can induce liver injury either by acting directly on the
liver cells or via chemoattraction of extrahepatic cells (e.g. neutrophils and
lymphocytes) (20) (Table 1, Fig. 1). During inflammatory conditions the expression
pattern of adhesion molecules is also changed in the Kupffer cells, similarly to the
sinusoidal endothelial cells. The most characteristic change is the downregulation of
PECAM-1 and the upregulation of ICAM-1 (Fig. 1) (26).
In addition to Kupffer cells the liver hosts a lymphocyte subpopulation termed pit
cells. (27) Their number in the liver is about 1% of the non-parenchymal cell
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population (28). The pit cells correspond to the natural killer NK cells in other
organs. Together they constitute the family of the large granular lymphocytes (LGL).
They probably originate form the bone marrow, circulate through the blood
and marginate in the liver, where they develop into pit cells by lowering their
density and increasing the number of granules. Pit cells remain in the liver about
two weeks and their survival is dependent on the presence of Kupffer cells (29).
Besides synthesis of IFN-γ upon triggering by the damaging noxae, the most
important function of the NK cells is the destruction of virus-infected and malignant
cells without previous activation. NK cells are able to migrate and transmigrate
through epithels. NK cells can be activated by interleukin-2. The resulting cell
population is known as lymphokine-activated killer cells (LAK) (2, 15).
The chemical mediators released by Kupffer cells and by hepatocytes attract
extrahepatic cells to the liver. Neutrophils (PMN) are the characteristic cellular
compound of the chemoattracted cells, and are involved in the acute inflammation
(Fig. 1). They are always present in the inflammatory infiltrate of chronic liver
disease. However, neutrophil infiltration is most prominent in alcoholic hepatitis
and extravasation and transmigration of neutrophils into the liver tissue are
critical for neutrophil-induced injury and cytotoxicity.
Up to now the role of T-lymphocytes in liver disease is still ill-understood.
Previously a role was suggested of T-cells in liver injury by activating Kupffer
cells to produce TNF-α (30) However there is also a considerable amount of data
demonstrating that T-cell activation against liver antigens (after a transient
cellular immune attack) induces tolerance and not immunity (31) and a recent
study suggests that at least natural killer T-cells might not concert in immunemediated liver injury (32). Furthermore, other studies described the liver as
graveyard for T-cells (33).
LIVER INFLAMMATION
Liver inflammation not only in many animal models (e. g. after CCl4 or
thioacetamide (TAA) administration) but also in humans may not be initiated by
the death of (apoptosis or necrosis) of liver parenchymal cells but by liver
resident and by recruited inflammatory cells. The hepatocellular stress induced by
hepatotoxins, or by viruses, may lead to activation of liver resident macrophages
on one side and to the release of chemokines on the other side (1, 2, 15).
Proinflammatory cytokines are Interleukin-1β, Interferon-gamma (IFN-γ), whose
tissue concentration increases early after toxin administration (34), followed by
Tumor Necrosis Factor-α, and Interleukin-6 in a similar kinetics, which are
released by natural killer cells as well as by Kupffer cells. They induce an
increased expression of cell adhesion molecules like ICAM-1 and VCAM-1 on
the portal and/or sinusoidal endothelial cells and a downregulation of PECAM-1
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(2). These molecules allow the recruitment and sinusoidal transmigration of
inflammatory cells toward their target, the hepatocyte (Fig. 1).
Inflammation perpetuates as long as the damaging noxae remain present or are
repeatedly administered. Leukocytes may enter the liver tissue mainly through
the portal tract, where the inflammation mainly initiates. The hepatic infiltrate
may include granulocytes, macrophages, but also T-lymphocytes, Blymphocytes, plasma cells (35). Resident and recruited inflammatory
macrophages can stimulate matrix synthesis by activated mesenchymal cells and
its deposition by the action of cytokines or growth factors, especially TNF-α,
TGF-β, and reactive oxygen intermediates/lipid peroxides (1, 2, 15).
COMPARISON OF CARBON-TETRACHLORIDE (CCL4)-INDUCED
LIVER DAMAGE WITH X-RAY-INDUCED LIVER INJURY
In an attempt to understand the mechanisms leading to recruitment of
inflammatory cells into the liver parenchyma we compared two models of liver
insult in the rat: administration of CCl4 on one side, and γ-irradiation applied
directly to the liver on the other.
After the administration of CCl4, levels of IFN-gamma rose 3-24 hours after
the treatment, followed immediately by TNF-α 6-24 hours after the treatment, the
levels of TGF-β were enhanced later 9-24 hours after the treatment (Table 2).
PECAM-gene expression was downregulated 24-48 hours after the treatment, and
ICAM was upregulated 9-48 hours after the treatment. IFN-gamma-treatment
decreased PECAM-1-gene-expression in isolated sinusoidal endothelial cells and
mononuclear phagocytes (MNPs) in parallel with an increase in ICAM-1-geneexpression in a dose and time dependent manner. In contrast, TGF-β-treatment
increased PECAM-1-expression. Additional administration of IFN-γ to CCl4Table 2. Comparison of the regulation of some inflammatory factors in CCl4-induced and X-rayirradiation induced liver damage.
Mediators and Adhesion
molecules
IL-1β
TNF-α
IL-6
TGF-β
CINC-1
IP-10
MIP-3α
KC
PECAM-1
ICAM-1
VCAM-1
CCl4-induced rat
liver damage
X-ray-induced rat
liver injury
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late ã
early ã
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ä
ã
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ã
ã
ã
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no change ã
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treated rats and observations in IFN-γ-/- mice confirmed the effect of IFN-γ on
PECAM-1 and ICAM-1-expression observed in vitro and increased the number
of ED1-expressing cells 12 h after administration of the toxin. The early decrease
of PECAM-1-expression and the parallel increase of ICAM-1-expression
following CCl4-treatment is induced by elevated levels of IFN-γ in livers and may
facilitate adhesion and transmigration of inflammatory cells. The up-regulation of
PECAM-1-expression in sinusoidal endothelial cells and mononuclear
phagocytes after TGF-β-treatment suggests the involvement of PECAM-1 during
the recovery after liver damage (26).
Similarly to CCl4 administration, a single irradiation of the rat liver induced
increase of several chemokines (e. g. CINC1 (IL-8), IP-10, MCP1, MIP-3α, MIP3β, MIG and ITAC) gene expression (Table 2). Moreover, CINC1 (IL8), MCP1
and IP-10 serum levels were significantly increased. In fact, irradiation of the
liver induces up-regulation of the genes of the main proinflammatory
chemokines, probably through the action of locally synthesized proinflammatory
cytokines. Nevertheless, the recruitment of inflammatory cells is not observed to
the irradiated rat liver (36).
Interestingly, significant radiation-induced increase of ICAM-1, VCAM-1,
junctional adhesion molecule-1 (JAM-1), β1-integrin, β2-integrin, E-cadherin,
and P-selectin-gene-expression could be detected in vivo in the irradiated rat liver,
while PECAM-1-gene-expression remained unchanged. These findings suggest
that liver irradiation modulates adhesion-molecules-gene-expression probably
through acute-phase-cytokines. However, PECAM-1 gene expression is not
affected. This may be one reason for the lack of the infiltration of extrahepatic
inflammatory cells after irradiation in this model (37), when compared to the
CCl4 or to acetaminophen induced inflammation (38).
LIVER DAMAGE REPAIR
When the injury is recurrent (or "chronic"), matrix deposition occurs in excess
of resorption as a result of an imbalance between fibrogenesis and fibrolysis
leading to scar formation. Herein chronic tissue destruction with missing or slow
regeneration also providing the space for matrix deposition may be of special
importance. As scarring progresses from bridging fibrosis to the formation of
complete nodules it results in an architectural distortion and ultimately in liver
cirrhosis. Liver fibrosis is a common sequel to diverse liver injuries such as
chronic viral hepatitis, ethanol, biliary tract diseases, iron or copper
accumulation. From the
toxic animal models of liver fibrosis we have learnt that fibrogenesis may
result from recurrent small liver injuries. These per se would result in complete
tissue repair, suggesting that activation of the fibrosis process with matrix
115
deposition may not be a primarily cellular problem but that of a recurrence of the
damaging noxae within a certain time window (2).
During liver damage a large number of cytokines are synthesised locally
among which TGF-β, TNF-α, platelet-derived growth factor and insulin-like
growth factor-I are thought to be of special importance for liver fibrogenesis.
The processes of liver repair and fibrogenesis resemble that of a wound-healing
process. Following injury and acute inflammation response takes place resulting in
moderate cell necrosis and extracellular matrix damage. After that tissue repair
takes place where dead cells are replaced by normal tissue with regeneration of
specialised cells by proliferation of surviving ones or generation from stem cells,
formation of granulation tissue, tissue remodelling with scar formation.
Liver fibrosis is defined as an abnormal accumulation of extracellular matrix
in the liver. Its endpoint is liver cirrhosis which is responsible for a significant
morbidity and mortality. Cirrhosis is an advanced stage of fibrosis, characterised
by formation of regenerative nodules of liver parenchyma separated by fibrotic
septa, which result from cell death, aberrant extracellular matrix deposition and
vascular reorganisation. Advanced liver fibrosis results in cirrhosis, liver failure,
and portal hypertension and often requires liver transplantation (1,2,15).
Accumulating data from clinical and laboratory studies demonstrate that even
advanced fibrosis and cirrhosis are potentially reversible. The hepatic stellate cells
have been identified as the pivotal effector cells orchestrating the fibrotic process
and, furthermore, reversibility appears to hinge upon their elimination (1, 2, 15).
Removing the insult and stopping the persistent inflammatory stimuli is
probably the best way to prevent progression of fibrosis; this has been shown in
many patients with chronic hepatitis C and in smaller numbers of patients with
autoimmune hepatitis. Clinical data confirmed that, providing appropriate,
targeted treatment to patients with histologically advanced liver disease,
especially those with autoimmune hepatitis, may improve their long-term
outcome (39-41). Furthermore, it was shown that, cirrhosis due to chronic
hepatitis B might be reversible in patients who respond to antiviral therapy (41).
Nevertheless, prevention of the progression of fibrosis to cirrhosis remains the
major clinical goal. The poor prognosis of cirrhosis is aggravated by the frequent
occurrence of hepatocellular carcinoma (2).
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R e c e i v e d : July 11, 2008
A c c e p t e d : July 23, 2008
Author’s address: Prof. Dr. G. Ramadori, Department of Internal Medicine, Section of
Gastroenterology and Endocrinology, Georg-August-University Göttingen, Robert-Koch-Straße
40, 37075 Göttingen, Germany; phone:+49-551-396301 fax: +49-551-398596; e-mail:
gramado@med.uni-goettingen.de