Cirrhosis of the Liver.

A molecular overview.

Sarah Coffano
Flavia Di Giallorenzo
Ambra Disabato Prof. Andrea Bartoli
 The liver

The liver is a voluminous extramural gland, its weight is about 2 kg. The
liver situated in the right hypochondrium, part of the epigastrium and a
small part of the left hypochondrium.
 …At the microscopic level: Stroma

This consist of two main parts:

- First, the liver is covered with a thin connective tissue capsule (of Glisson) which contains regulary arranged collagenic
fibers and scattered fibroblasts;
- Second, at the hilus of the liver the connective tissue of the capsule extends like the trunk of a tree into the parenchyma
of the liver.
Structure of lobules
The parenchyma presents a characteristic cordonal structure
with the hepatocytes united to form branches and
anastomosed lamellae between them.
The parenchyma is organized in:
• Classic lobule: is pyramidal element formed by the
cellular laminae and by the sinusoids that converge
towards into centrolobular vein. On the periphery of the
lobule there are the fine interlobular ramifications of the
elemnts of the hepatic peduncle a branch of the
hepatic artery, a branch of the portal vein and a biliary
canaliculus.
• Portal lobule: in this case we refer to the parenchyma
which is enclosed by a triangular structure, whose three
vertices correspond to three centrolobular veins.
• Liver acinus: is the portion of the hepatic parenchyma
between two centrolobulary veins. The vertices formed
by the centrolobular veins and by two harbor spaces.
 What is present in the liver?
The other cells are:
• Kupffer cells, are macrophages with cytoplasm rich in
lysosomes
• Stellate cells, are the main storage site of vitamin A;
moreover they are activated during hepatic damage and
they carry out the fibrogenesis.
The hepatocytes is a polyedral epithelal cells.
There are two poles:
 Vascular are the faces in contact with the
sinusoids and present numerous microvilli;
 Biliary are the faces in contact with the other
hepatocytes that have deep showers, for union
of these showers are formed the bile
canaliculus.
Hepatic sinusoid: the endothelium is
discontinuous, it has spaces between one cell and
another. These allow the plasma to exit the
vascular lumen and go into spaces of Disse, where
the microvilli of the hepatocyte protrude. Thanks
to microvilli the hepatocyte can take from the
plasma the substance necessary for its activities.
Liver regeneration

▪ The liver is the only

visceral organ that
possesses the
remarkable capacity to
regenerate.
▪ The liver can
regenerate after either
surgical removal or
after chemical injury. It
is known that as little
as 25% of the original
liver mass can
regenerate back to its
full size.
Liver regeneration

▪ Liver regeneration involves replication of the liver cells, mainly hepatocytes,

followed by other cells such as biliary epithelial cells and sinusoidal
endothelial cells.
▪ Once cell proliferation is completed, the newly divided cells undergo
restructuring, angiogenesis and reformation of extracellular matrix to
complete the regeneration process. Interestingly, in most cases, liver function
is only partially affected during liver regeneration. Whereas certain
specialized functions such as drug metabolism decrease, many other primary
functions such as albumin and bile production are not substantially affected.
The ability for the liver to regenerate is central to liver homeostasis. Because the liver is the
main site of drug detoxification, it is exposed to many chemicals in the body which may
potentially induce cell death and injury. The liver can regenerate damaged tissue rapidly
thereby preventing its own failure.
Liver regeneration

Cytokine, growth factor, and metabolic

networks during liver regeneration.
Efficient liver regeneration involves three
networks; cytokine (yellow), growth factor
(red), and metabolic (white).
Representative molecules that participate in
each network are shown with activation
profiles drawn as a waves, indicating that
networks are only transiently activated after
partial hepatectomy.
Liver regeneration is technically a
process of compensatory growth rather than regeneration.

▪ As such, it does not follow the same general steps involved in true
regenerative processes, and formation of a blastema containing
dedifferentiated cells does not occur.
▪ The extent to which these cells contribute to regeneration varies
according to the nature of the injury, doses of inducing agents, or
other experimental variables.
Autonomy and Timing of Regeneration

▪ The extent and timing of liver regeneration are known to vary

according to circadian rhythms; a recent study has identified a
mechanism by which these rhythms control hepatocyte proliferation
after PH.
▪ A fascinating counterpart to these observations is that the timing of
DNA replication, which is not under the control of circadian rhythms,
appears to be an intrinsic property of hepatocytes. Infact the timing
of hepatocyte DNA replication after PH is an autonomous process,
primarily guided by intrinsic signals.
 The Cytokine Network and the Initiation of
Liver Regeneration

Cytokine pathways activated during liver regeneration. The figure illustrates

interactions in cytokine pathways between Kupffer cell and hepatocytes in the
regenerating liver. TNF binds its type I receptor on Kupffer cells, leading to the
activation of NF-kB. C3a, C5a, and MyD88 also can activate NF-kB after PH. Il-6
and Tnf are both NF-kB target genes; IL-6 is subsequently released into the
serum, and binds to its receptor, a complex of gp80 and gp130 subunits, on
hepatocytes. Activation of gp130 leads to phosphorylation of STAT3 monomers
by Janus-associated kinases (JAKs). STAT3 then homodimerizes and translocates
to the nucleus, where it induces transcription of a number of target genes,
including Socs3, which then inhibits further STAT3 phosphorylation. SCF also
may activate STAT3 after PH. In parallel with STAT3 phosphorylation, gp130
activation also leads to a signaling cascade involving the phosphorylation of
ERK1/2 and the upregulation of multiple genes important for regeneration. TNF,
tumor necrosis factor; NF-kB, nuclear factorkappaB; MyD88, myeloid
differentiation factor 88; PH, partial hepatectomy; IL-6, interleukin-6; STAT3,
signal transducer and activator of transcription 3; SCF, stem cell factor.
Growth Factors and Cell Cycle Progression

Growth factor signaling pathways

during liver regeneration. Stimulation
of the tyrosine kinase receptors for HGF
(c-met), and the EGF ligands, TGF, HB-
EGF, and AR, (EGFR) activates
numerous intracellular signaling
pathways that regulate transcription
factors involved in liver regeneration.
mTOR and its inhibitor rapamycin
modulate translational control of these
pathways. HGF, hepatocyte growth
factor; EGF, epidermal growth factor;
TGF, transforming growth factor alpha;
HB-EGF, heparin-binding EGF-like
growth factor; AR, amphiregulin;
mTOR, mammalian target of
rapamycin.
Interactions Between Cytokines and Growth
Factors During Liver Regeneration

▪ One important linkage between cytokines and growth factors may be

the activation of matrix metalloproteinases (MMPs) by cytokines, such
as TNF.
▪ The sequential activation of cytokine and growth factor receptors may
stimulate numerous intracellular signaling pathways needed for cell
survival and proliferation.
Interactions Between Cytokines and Growth
Factors During Liver Regeneration

Mechanism for EGFR activation through

TACE activity. TNF binding to its receptor
activates NF-B and Akt, stimulating
cytokine production and survival pathways
(left panel). TNF also activates TACE,
which cleaves membrane-bound TGF. The
cleaved, active TGF molecule binds to and
activates the EGFR, a receptor tyrosine
kinase, leading to downstream activation
of ERK1/2 (right panel). Cooperation
between cytokine (TNF) and growth factor
(EGF ligands) signaling activates pathways
that are needed for hepatocyte survival,
growth, and proliferation. EGFR,
epidermal growth factor receptor; TACE,
transforming growth factor alpha
converting enzyme; NF-B, nuclear factor-
kappaB; TNF, tumor necrosis factor; TGF,
transforming growth factor alpha; ERK1/2,
extracellular signal-regulated kinase 1/2.
Cirrhosis of the liver is a pathologic entity that has three features:
 Hepatic necrosis sufficient to destroy total lobules in at least two third
of the liver.

 Major scarring as a result of this necrosis which becomes a permanent

type of connective tissue.

 Formation of new liver through the process of regeneration.

As a result, the architecture of the

liver is completely destroyed and is
largely formed of scars and
regenerative nodules.
Vascular Changes.
The alteration of vascular pattern is the major determining factor in
cirrhosis. In fact, cirrhosis develops when nodules of parenchyma are formed
with all the pre-existing vascular afferent and efferent on the periphery.

 Metabolites and toxins may escape into systemic

circulation
 Particulate matter is not adequate filtered by the
Kupffer cells
 Escape of antigens into the systemic circulation leads
to hypergammaglobulinaemia and favourite the
passage of bacteria through the liver accounts.
Vascular Changes.

In healthy liver…
the terminal portal tract blood runs
through hepatic sinusoids where fenestrated
sinusoidal endothelia that rest on loose
connective tissue (space of Disse) allow for
extensive metabolic exchange with
the lobular hepatocytes; sinusoidal blood is
collected by terminal hepatic venules that
disembogue into one of the three hepatic veins
and finally the caval vein.
Vascular Changes.
In cirrhotic liver…
activated myofibroblasts that derive from perisinusoidal
hepatic stellate cells and portal or central-vein
fibroblasts proliferate and produce excess extracellular
matrix (ECM). This event leads to:
- fibrous portal-tract expansion
- capillarisation of the sinusoids
- central-vein fibrosis
Blood is directly shunted from terminal portal veins and
arteries to central veins, with consequent (intrahepatic) portal
hypertension and
compromised liver synthetic function.
Damage and loss of liver cells.

Liver cells become directly damaged by

some toxic agents.

These undergo enlargement and may contain more

than one nucleus, or a nucleus of convoluted type,
and they proliferate by mitotic division. In this way
hypertrophic areas are formed and the loss of liver
Silver stain shows collapse of the reticulin substances may be in part compensated for.
framework indicating major loss of liver cells.
Damage and loss of liver cells.

In the course of this inflammatory process, the

liver cells die more frequently due to
programmed cell death (apoptosis) and necrosis.
The result is increased cell growth through a
hyperplastic state also referred to as
compensatory proliferation, which can lead to
tumor development.

The destruction of cells may be more marked at one

part of the lobule than at another and some lobules may
be completely destroyed. As a result of this damage, the
architecture of the lobules thus becomes greatly
distorted.
Fibrogenesis.
The cirrhotic liver shows an increase in all collagen types
irrespective of the aetiology..

The scar tissue in cirrhosis is composed of a complex

assembly of different extracellular matrix molecules
(ECM), consisting of:
o fibril-forming interstitial collagens type I and III
o basement membrane collagen type IV
o non-collagenous glycoproteins such as fibronectin
and laminin
o elastic fibres
o glycosaminoglycans and proteoglycans
 Fibrogenesis.
Initially, fibrogenesis is counterbalanced by removal of
excess ECM by proteolytic enzymes, such as specific
matrix metalloproteinases (MMPs).

Chronic damage usually favours fibrogenesis over

fibrolysis, with an upregulation of tissue inhibitors of
MMPs (TIMPs).

The major hepatic ECM-producing cells are

myofibroblasts that either derive from activated hepatic
stellate, which activation is mediate by fibrogenic
cytokines and growth factors that are released by
activated macrophages (Kupffer cells) and other
inflammatory cells.
 Cells partecipating to FIBROGENESIS are

Hepatic Stellate Cells (HSCs)

Non-parenchimal
Liver sinusoidal endothelial cells (LSECs)
cells

Kupffer cells (KCs)

Hepatocytes Parenchimal cells

Liver Sinusoidal Endothelial Cells or LSECs
They constitute the sinusoidal wall, known as endothelium. The structural characteristic of
LSECs is the fenestrae on the surface of the endothelium. These fenestrae act as a dynamic filter,
facilitating the exchange of fluids, solutes and particles between sinusoidal blood and the
parenchymal cells.

Liver injury results in defenestration and a decrease in the number

of fenestrae. In cirrhotic liver, defenestration of sinusoidal
endothelium and the presence of a subendothelial basement
membrane are frequently present.
Defenestration and capillarization of the hepatic endothelium are
believed to be important in the initiation of perisinusoidal fibrosis
by altering retinol metabolism.
Kupffer Cells or KCs:
are specialized macrophages located in the lining walls of the sinusoids of the liver that form part of
the reticuloendothelial system.
Reactive oxygen radicals are released by hepatic macrophages after activation with cytokines,
LPS and prostaglandins as a defence against bacterial invasion. These molecules have been
implicated in the pathogenesis of liver injury and fibrogenesis.
Kupffer cells are involved both by producing cytokines and growth factors that induce HSC
myofibroblastic transformation and by regulating the production of metalloproteinases and
their inhibitors.
In fact, KC-derived TGF-β1 has an important role in the induction of the collagen and
proteoglycan production.

Another mechanism that could lead to the phenotypic change of Ito cells is the production of
gelatinases by Kupffer cells. In fact activation of KCs and secretion of gelatinase degrades
collagen type IV, which does not induce HSCs transition, triggers the HSCs phenotypic
change.
TGF-β: derive from activated Kupffer cells and damaged hepatocytes. is recognized
as a major profibrogenic cytokine and is a potent inducer of HSCs
proliferation and collagen production.

TGF-β binds to TGF-β1 receptor type II (TbR-II)

and recruits the TGF-β1 receptor type I (TbR-I).
TbR-I subsequentely phosphorylates Smad2
and Smad3 which form hetero – oligomers with
Smad4.
They translocate from the cytoplasm to the
nucleus, where they regulate transcription of
the target gene.
Hepatocytes
They are target for most hepatotoxic agents, including hepatitis virus, alcohol metabolites, and bile acids.
Damaged hepatocytes release reactive oxygen species (ROS) and fibrogenic mediators, induce activation
of HSCs, and stimulate the fibrogenic actions of myofibroblast.

Apoptosis of hepatocytes is a common event in liver injury and contributes to tissue inflammation,
fibrogenesis, and development of cirrhosis.

are a critical determinant of endothelial dysfunction and is due to disturbed

balance between oxidant and antioxidant enzymes. ROS are involved in necrosis
and apoptosis of hepatocytes and HSC activation.
They mediate the onset of Hapatocellular Carcinoma.
 Hepatic Stellate Cells or HSCs
Reside in the space of Disse, in healthy liver, and their main function is the storage of
During liver injury, HSCs lose their
vitamin A and other retinoids.
vitamin A content and undergo activation triggered
by exposure to cytokines and growth factors, such as
platelet-derived growth factor (PDGF) and transforming
growth factor (TGF)-β1. Activation consists of two major
phases:
- Initiation or “preinflammatory stage”
- Perpetuation

Sustained activation involves at least seven discrete changes in

cell behavior: proliferation, chemotaxis, fibrogenesis,
contractility, matrix degradation, retinoid loss, and WBC
chemoattractant/cytokine release.
PDGF: (Platelet-Derived-Growth-Factor)
Its signaling is among the best characterized pathways of HSC activation
PDGF binds its receptors, the receptor subunits dimerize with subsequent
phosphorylation of the tyrosine residues in the intracellular domain.
This leads to Ras-MAPK pathway activation, signaling through
the PI3K-AKT/PKB pathway and mobilization of intracellular calcium ions to activate PKC
family members
All these events ultimately lead to cellular proliferation. This is followed by development
of a contractile, fibrogenic phenotype that correlates with the degree of fibrosis and
inflammation
 Chemokines:
are a class of small chemotactic molecules with cytokine-like functions, which are well
known to orchestrate inflammatory responses within different organs . Multiple effector
cells in liver fibrosis are potential targets and sources of chemokines, each expressing a
different combination of receptors and ligands.
HSCs express several chemokines receptors including CXCR3, CCR5, and CCR7, and secrete
numerous chemokines, including CCL2, CCL3, CCL5, CXCL1, CXCL8, CXCL9 and CXCL10.

In general, chemokines promote the migration

of fibrogenic cells to the site of injury, thereby
enhancing fibrogenesis through increased cell
number and amplified inflammation.
Etiology
Liver cirrhosis has many possible
causes; sometimes more than one
cause is present in the same
person.
▪ 40% is attributable to either
hepatitis B or hepatitis C
▪ 21% is attributable to alcohol
consumption
Alcoholic liver disease once was considered
to be the predominant source of cirrhosis
but hepatitis C has emerged as one of the
leading cause of chronic hepatitis and
cirrhosis.
 Etiology: Alcohol liver disease

Alcoholic cirrhosis develops for 10–20% of

individuals who drink heavily for a decade or
more.

• Alcohol seems to injure the liver by blocking the normal metabolism of

protein, fats, and carbohydrates.
• This injury happens through the formation of acetaldehyde from alcohol which
itself is reactive, but which also leads to the accumulation of other reactive
products in the liver.
• Patients may also have concurrent alcoholic hepatitis with fever,
hepatomegaly, jaundice, and anorexia.
Etiology: Non alcoholic steatohepatitis (NASH)

▪ In NASH, fat builds up in the liver and eventually causes scar tissue.
▪ This type of hepatitis appears to be associated with obesity diabetes,
protein malnutrition, coronary artery disease, and treatment with
steroid medications.

This disorder is similar in it signs to alcoholic liver disease,

BUT the patient does not have an alcohol history.
Etiology: Chronic hepatitis C

Hepatitis C virus (HCV) is one of 6 viruses (along with hepatitis A, B, D, E, and

G viruses) that cause viral hepatitis. Prior to identification of the virus, it was
termed non-A/non-B hepatitis to distinguish it from the viral causes of
nonalcoholic hepatitis that were known at the time.

▪ Infection with the hepatitis C virus causes inflammation of the liver and a
variable grade of damage to the organ.
▪ Over several decades, this inflammation and damage can lead to cirrhosis.
Among patients with chronic hepatitis C, 20–30% will develop cirrhosis.
Cirrhosis caused by hepatitis C and alcoholic liver disease are the most
common reasons for liver transplant.
Etiology: Chronic hepatitis B

Hepatitis B infection is a worldwide healthcare problem, especially in

developing areas. The hepatitis B virus (HBV) is commonly transmitted via
body fluids such as blood, semen, and vaginal secretions.
The hepatitis B virus causes liver inflammation and injury that over several
decades can lead to cirrhosis.
Hepatitis D is dependent on the presence of hepatitis B and accelerates
cirrhosis in co-infection.
Etiology: other possible causes

Miscellaneous causes of cirrhosis include:

▪ Autoimmune hepatitis
▪ Primary biliary cirrhosis
▪ Secondary biliary cirrhosis - Associated with chronic extrahepatic bile duct obstruction
▪ Primary sclerosing cholangitis
▪ Hemochromatosis
▪ Wilson’s disease
▪ Alpha-1 antitrypsin deficiency
▪ Type IV glycogen storage disease
▪ Drug-induced liver disease
Liver cirrhosis and related
complications
Complications

▪ Hepatic encephalopathy
▪ Hepatorenal Syndrome
▪ Ascites
▪ Portal Hypertension
▪ Hepatocellular carcinoma
Hepatic encephalopathy
Hepatic encephalopathy (HE) is a brain dysfunction
that affects individuals with liver failure. These
patients have a liver incapable of eliminatig waste
substances from blood, whose accumulation leads to
deterioration of the nerve cells.
There are various type of HE:
▪ A (or acute) the main morbid conditions that
accompany acute HE are: the acute fulminant viral
hepatitis; toxic hepatitis caused by the use of drugs,
alchol and the Reye’s sindrome
▪ B (from transjugular itrahepatic portosystemic
shunt)
▪ C (or chronic) is usually related to liver cirrhosis
Clinical manifestations

The clinical manifestations of HE range from

minimal changes in personality and motor
activity, to overt deterioration of intellectual
function, decreased consciousness and coma.

There are also morphological changes in

astrocytes :
Their nuclei are enlarged, have sparse marginal
chromatin, and often contain an excess of
glycogen. This is the form of Alzheimer type 2
glia cells.
Molecular mechanisms involved in pathogenesis

Hepatic encephalopathy complicating

chronic liver failure appears to be
associated with a shift in the balance
between inhibitory and excitatory
neurotransmission towards a net increase
of inhibitory neurotransmission.
Ammonium also plays an important role in
pathogenesis because increased
concentrations trigger a sequence of
metabolic.
 Glutamatergic neurotrasmission

The process begins with:

• The astrocyte which remove both ammonium and
glutamate from the extracellular spaces of the central
nervous system and they supply glutamine to neurons;
• The astrocytes eliminates ammonium by metabolizing
glutamate to glutamine in a metabolic process
catalyzed by glutamino-synthase, an ATP-dependent
enzyme;
• Glutamine is captured by neurons where it is used for
the synthesis of glutamate and inderectly also gamma-
aminobutyric acid (GABA).

 It has also been hypothesized that the accumulation of intracellular glutamine may result in astrocytic swelling and mild forms of
cerebral edema also in C-type hepatic encephalopathy. An excess of ammonium in the brain also causes an increase in
neosynthesis and the release of glutamate. Excessive concentration of this in the extracellular spaces of the brain can become
toxic to neurons (excitotoxicity).
 GABA-ergic system
Ammonium also causes significant alterations in the GABAergic inhibitory transmission.
It is also able to induce in association with other factors such as mercaptans, phenols, oxindole
or other tryptophan derivatives a hypersensitivity of the GABAergic receptor complex.
▪ The receptor complex of the GABAa channel of
CL- includes, in addition to sites for the
recognition of GABA, also those for
benzodiazepines, BZD.

▪ In the presence of GABA, activation of these

sites facilitates the opening of the Cl- channel
and the following sedative effects such as CNS
inhibition.

 This concept suggested the use of BZD antagonists as

symptomatic drugs in treatment in experimental
hepatic encephalopathy
 Effects of ammonia accumulation in HE

Prolonged exposure to increased concentrations of ammonia in HE cause metabolic events that may lead
to irreversible neuronal dysfunction and damage.

• generation of NO leads to enhanced accumulation of peroxides and

reduction of the activity of antioxidant enzymes, resulting in oxidative stress
and nerve cell damage;

AMMONIA INDUCES • down-regulates NMDA receptors. The decreased Glu receptor density likely
contributes to decreased excitatory transmission in HE. In chronic HE, an
increased extracellular accumulation of Glu (or Asp) is attributed to impaired
Glu re-uptake by cerebral astrocytes and nerve endings. Inhibition of
astrocytic Glu uptake has been attributed to decreased expression of the
astroglia-specific Glu transporter, GLT-1.
 Consequences
Have been shown by in vivo brain microdialysis that
chronic, mild hyperammonemia in rats inhibits NMDA-
induced liberation of cGMP into the extracellular space.
This finding was interpreted as reflecting an ammonia-
evoked impairment of the glutamate–NO–cGMP pathway.
Since this pathway is involved in long-term potentiation
(LTP), a phenomenon underlying memory formation, its
inhibition may contribute to HE-related deficits in
intellectual and memory function of humans.
 Hepatorenal Syndrome (HRS)
Consists in rapid deterioration of kidneys functions in absence of structural kidney abnormalities.

As cirrhosis progresses, kidneys are no longer able to maintain the volume of extracellular
fluids within normal parameter and glomerular filtration resistance increases.
This is caused by an abnormal increase in tubular sodium that leads to a disproportionate
increase in total blood water relative to total sodium content.

The mechanism that triggers HRS includes both increased

vasoconstrictor and decreased vasodilator factors acting on the
renal circulation.

The endogenous vasodilators may be:

• Nitric oxide
• Carbon monoxide
• Glucagon
• Adrenomedullin
• Endothelin – 1
There is a decrease in the systemic vascular resistance due
to the arterial splanchnic vasodilation that is compensated
by the increase in heart rate and in cardiac output (the so-
called “hyperdynamic circulation”).
However, as the liver disease progresses leading to a further
impairment in portal hypertension and hepatic failure, the
hyperdynamic circulation is no longer adequate to
compensate the severity of the reduction of the effective
blood volume due to the splanchnic arterial vasodilation.
This leads to a further activation of the systemic
endogenous vasoconstrictor systems:
• RAAS
• Non-osmotic release of VP and so Hyponatremia.

Activation of vasoconstrictor leads to the retention of

sodium and free water.
 .

Retention of nitrogenous toxins

Fluid overload with dilutional hyponatremia

Accumulation of urea and consequent increased

production of ammonia that could trigger the
onset of hepatic encephalopathy

Sodium and water retention leading to ascites

 condition of pathologic fluid collection within the abdominal cavity that
Ascites: represents a state of total-body sodium and water excess.

 Underfilling Theory: primary abnormality is inappropriate sequestration of fluid within the

splanchnic vascular bed due to portal hypertension and a consequent decrease in effective
circulating blood volume. This activates the plasma renin, aldosterone, and sympathetic nervous
system, resulting in renal sodium and water retention.
 Overflow Theory: the primary abnormality is inappropriate renal retention of sodium
and water in the absence of volume depletion. In fact, in affected people intravascular hypervolemia
can be observed.
 Peripheral arterial vasodilation hypothesis: . It suggests that portal
hypertension leads to vasodilation, which causes decreased effective arterial blood
volume. As the natural history of the disease progresses, neurohumoral excitation
increases, more renal sodium is retained, and plasma volume expands. This leads to
overflow of fluid into the peritoneal cavity.
The vasodilation theory proposes that
underfilling is operative early and overflow is
operative late in the natural history of
cirrhosis.
So the arterial blood volume is less than effective if peripheral vasodilatation occurs. This
is manifested by decreased peripheral vascular resistance and thus decreased arterial
blood volume which leads to activation of three compensatory pathway:

Activation of Sympathetic Nervous System that leads to stimulation of the

following point.

Renin-Angiotensin-Aldosterone system or RAAS.

Non-osmotic release of Arginine Vasopressine (AV).

 is caused by impaired delivery of filtrate to the distal nephron because of
increased proximal sodium reabsorption and increased plasma levels of AVP .
 Portal Hypertension
Scarring narrows and compresses hepatic sinusoids.
There’s a progressive increase in resistance to portal
venous blood flow results in Portal Hypertension. As
pressure increases, blood flow decreases and the
pressure in the portal system is transmitted to its
branches. This results in dilatation of venous
tributaries.
- Increased blood flow through collaterals
- increased in cardiac output
- increased total blood volume
- decrease in systemic vascular resistance .

Phenotypic changes in hepatic cells such as liver sinusoidal endothelial cells

(LSECs) and hepatic stellate cells (HSCs) have a key role in increased
intrahepatic vascular resistance.
When activated they turn to myofibroblast and become contractile. Increased
recruitment of these HSCs around newly formed sinusoidal vessels increases
intrahepatic vascular resistance. Furthermore, activated HSCs display a decreased
response to vasodilators.

This augments intrahepatic resistance to portal blood flow and

facilitates the development of portal hypertension.
 lead to impaired vasomotor control.
Decreased presence of vasodilators:. such as NO (nitric oxide) which
bioavailability is diminished in cirrhosis through two ways:
• eNOS is inhibited by negative regulators such as caveolin-1 that are up-
regulated during cirrhosis.
• Increased ROS spontaneously react with NO to form peroxynitrite
(ONOO-) an endogenous toxicant.
This contributes to increase intrahepatic vascular resistance

Increased presence of vasoconstrictors: such as thromboxane A2 (TXA2).

TXA2 is produced by the action of COX-1 in LSECs.
The activity of COX-1 increases during cirrhosis, resulting in greater quantities of TXA2 and
thereby increased intrahepatic vascular resistance.
Another important vasoconstrictor is ET-1 (endothelin-1) which has its receptors on HSCs.
ET-1 belongs to a family of 21 amino-acid peptides that are potent long-acting
vasoconstrictor.
Endothelin-1 (ET-1) mediates both vasodilation and vasoconstriction through ET-1 receptors
in the intrahepatic/sinusoidal microcirculation.
• Endothelin type-A receptors (ETRAs), residing on hepatic stellate cells (HSCs) and
mediate vasoconstriction.
• ET type-B receptors (ETRBs) induce both vasoconstriction and vasodilation
depending on their cellular location.
• ETB1 receptors, which reside on endothelial cells, cause vasodilation through nitric
oxide (NO) production.
• ETB2 receptors on HSCs
vasoconstriction.