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Recent Advancements in Diagnosis and Therapy of Liver Cirrhosis

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REVIEW ARTICLE

Recent Advancements in Diagnosis and Therapy of Liver Cirrhosis

Roberto Giulio Romanelli and Cristina Stasi*

Department of Experimental and Clinical Medicine (DMSC) and Liver Unit; University of Florence- School of Medi-
cine, Azienda Ospedaliero Universitaria Careggi - AOUC Largo Brambilla, no. 3 I-50134 - Firenze Italy

Abstract: Cirrhosis is a diffuse pathophysiological state of the liver considered to

ARTICLE HISTORY
Received: May 26, 2015
Revised: October 07, 2015
Accepted: November 20, 2015
DOI:
10.2174/138945011766616061310
1413
be the final stage of various liver injuries, characterized by chronic necroinflamma-
tory and fibrogenetic processes, with subsequent conversion of normal liver archi- Please provide
corresponding author(s)
tecture into structurally abnormal nodules, dense fibrotic septa, concomitant paren- photograph
size should be 4" x 4" inches
chymal exaustment and collapse of the liver tissue. Alcoholic liver disease and
chronic infections due to HBV and/or HCV constitute the main causes of liver cir-
rhosis worldwide. During a lag time of 15 to 30 years, chronic liver diseases can
lead to liver cirrhosis and its complications. Active hepatic inflammation plays a
pivotal role in the inflammation-necrosis-regeneration process, which eventually
leads to liver cirrhosis and hepatocellular carcinoma. Prognosis of liver cirrhosis is
highly variable and influenced by several variables, such as etiology, severity of liver disease, pres-
ence of complications and co-morbidities. In advanced cirrhosis, survival decreases to one or two
years. Correct advanced diagnosis and selected treatment with different molecules may help in under-
standing mechanisms of fibrogenesis, the driving forces of cirrhosis’s pathogenesis, and the scrupu-
lous approach to more effective therapeutic procedures. Prevention of fibrosis with further deteriora-
tion of liver function through specific treatments is always required, through the removal of the under-
lying causes of liver disease. Advanced liver disease, with subsequent complications, requires targeted
treatment. Therefore, the aim of this review is to assess the diagnosis and treatment of liver cirrhosis
on the pathophysiological bases, searching for relevant studies published in English using the PubMed
database from 2011 to the present.

Keywords: Liver cirrhosis, transient elastography, fibrosis, liver, complications.

INTRODUCTION architecture frequently occurs. In current practice, common

From a clinical point of view, liver cirrhosis (from greek
κιρρος, yellowish) is the end stage of various reiterated liver
injuries (wounding response) which lead to a massive prolif-
eration of connective tissue in the parenchymal liver com-
partment. This is caused by the necro-inflammatory and fi-
brogenetic processes typical of the long course of all chronic
liver disease. This clinical syndrome derives from exoge-
nous/toxic causes, infections, toxic/allergic processes, im-
munopathological/autoimmune causes, vascular processes or
inborn errors of metabolism. The pathological process of
liver cirrhosis is characterized by diffuse nodular regenera-
tion that replaces normal liver architecture, together with the
production of dense fibrotic septa, concomitant parenchymal
exhaustment, and the final collapse of the liver tissue. Even-
tually, the organ’s original structure is completely lost and a
concomitant profound distortion of the hepatic vascular
end stage liver disease (ESLD) due to many forms of chronic
liver disease (CLD) is usually accompanied by a variety of
only partially manageable complications (i.e., ascites, he-
patic encephalopathy, portal hypertension and the onset of
gastro-esophageal varices, thrombocytopenia, jaundice and
hepatic failure) and some life-threatening complications,
such as gastrointestinal bleeding and hepatocellular carci-
noma, some of which capable to decrease survival rate [1].
Necro-inflammatory-regenerative processes through inter-
mediately active hepatic inflammation leads to cirrhosis in a
period of time ranging from 10 to 30 years.
Other causes of liver cirrhosis include inherited diseases,
such as hemochromatosis and Wilson’s disease, autoimmune
processes, such as primary biliary cholangitis and primary
sclerosing cholangitis, and autoimmune hepatitis [2-6].
EPIDEMIOLOGY

*Addresss correspondence to this author at the Department of Experimental
and Clinical Medicine (DMSC) and Liver Unit; University of Florence-
School of Medicine, Azienda Ospedaliero Universitaria Careggi - AOUC
Largo Brambilla, no. 3 I-50134 - Firenze, Italy; Tel: +39-55-4271076; Fax:
+39-55-417123; E-mail: cristina.stasi@gmail.com
The prevalence of CLD is increasing worldwide. In 2010,
liver cirrhosis was the 23rd cause of death worldwide (31
million), Disability Adjusted Life Years with roughly equal
proportions attributable to HCV, hepatitis B virus (HBV)
and alcohol consumption [7]. According to a report of the

1389-4501/16 $58.00+.00 © 2016 Bentham Science Publishers

2 Current Drug Targets, 2016, Vol. 17, No. 12
National Center for Health Statistics, liver cirrhosis and
chronic liver diseases were the twelfth leading cause of death
in the United States in 2011 [8]. Changes in mortality for
cirrhosis in different countries reflect differences in the
prevalence of risk factors such as alcohol abuse and HBV
and hepatitis C virus (HCV) infection. However, no informa-
tion was available for 31% of countries. Therefore, the
global burden of liver cirrhosis was underestimated [9, 10].
In western countries, the most frequent causes of liver cir-
rhosis are chronic viral hepatitis, due to HBV or HCV, alco-
hol abuse and, more recently, obesity, non-alcoholic fatty
liver disease (NAFLD), and non-alcoholic steatohepatitis
(NASH) alone or together with the exposure to liver viral
infections and/or alcholism (alcoholic steatohepatitis, ASH)
[11, 12].
Chronic HBV and HCV infections account for 57% of all
liver cirrhosis cases [13]. Mortality rate due to liver cirrhosis
and its complications (decompensated liver cirrhosis, liver
failure, and hepatocellular carcinoma -HCC-) in chronically
virus-infected people is about 1 million a year [14].
PATHOPHYSIOLOGY
Liver cirrhosis is characterized by the presence of fibrous
septa between the portal fields, (active and passive septa,
both porto-portal and porto-central ones), regenerative nod-
ules and the extreme abnormality of liver architecture (Fig. 1
and 2). All this may lead to the collapse of the organ and
vascular rearrangements (the sinusoidal remodeling, the cap-
illarization of sinusoids, the formation of intrahepatic shunts,
due secondary to angiogenesis and necrosis/apoptosis of
parenchymal cells). These alterations are already present in
an early phase of the disease, but remain undetected for a
long time. Liver cirrhosis may be classified into two phases,
the compensated one and the decompensated one. During the
compensated phase, there are no symptoms and portal pres-
sure is still below the limit for the onset of ascites and
varices. In the second decompensated one, portal pressure
increases much more above the limit for the development of
clinically evident complications of portal hypertension and
patients are at risk to develop life-threatening complications
(ascites, varices, sepsis, especially spontaneous bacterial
peritonitis, encephalopathy, non obstructive jaundice, hepa-
tocellular carcinoma) [15]. Contributing factors are repre-
sented by an imbalance among vasodilating (especially nitric
oxide) and vasoconstricting (especially endothelins) mole-
cules, which eventually leads to increased intrahepatic resis-
tance and portal hypertension. Hemodynamic complications
of liver cirrhosis are frequently observed when the hepatic
venous pressure gradient (HVPG) is higher than 10 mmHg
[16]. Portal hypertension arises from the concomitant in-
crease in portal flow resistance due to deposition of fibrous
scar within the liver compartment and the so-called vascular
dysfunction.
Ascites is principally due to the incapacity of urinary de-
livery of dietary sodium with a positive sodium balance (so-
dium and water retention). Water retention, in this phase,
follows sodium retention to maintain fluid osmolality in the
physiological range. Sodium and water retention, thus, are
due to a complex circulatory dysfunction, which in turn is
secondary to the established portal hypertension, and is
Romanelli and Stasi
called “hyperdynamic circulatory dysfunction”. Cirrhotic
patients with portal hypertension and the portal-systemic
collaterals at different levels are characterized by the pres-
ence of peripheral arterial vasodilation, especially in the
splanchnic compartment, characterized by increased venous
pre-load and cardiac output, together with decreased periph-
eral arterial resistances. The syndrome is characterized by a
decreased “effective arterial blood volume” (EABV), sensed
by arterial and cardio-pulmonary volo- and baro-receptors of
the central cardio-thoracic compartment. As a consequence,
there is the progressive homeostatic activation of vasocon-
stricting and antidiuretic vasoactive systems, such as the
renin-angiotensin-aldosterone system and the sympathetic
nervous system, which, in turn, creates, together with a non-
osmotic antidiuretic hormone (ADH) release, a vicious circle
that contributes to a further increase in sodium and water
retention. Initial sodium retention occurs in the distal part of
the kidney, due to increased plasma levels of aldosterone, but
with the ongoing circulatory dysfunction, even the proximal
tubuli of the kidney are involved. This phenomenon is the
basis for the fluid accumulation in the peritoneal cavity and
the formation of ascites, due to increased portal pressure, and
its eventual resistance to diuretic treatment. In liver cirrhosis,
both portal hypertension and splanchnic vasodilation, due to
increased release and production of nitric oxide, contribute to
the onset and the maintenance of ascites [17]. Proximal so-
dium retention and the non-osmotic release of ADH, due to
hypovolemia, trigger free water retention and the consequent
hyponatremia. Renin angiotensin aldosterone (RAA) and
sympathetic nervous system hyperactivity decrease renal
perfusion and represent the biochemical and hormonal basis
for the onset of hepatorenal syndrome. Renal effects of vaso-
constricting agents are counteracted by an increase in the
release of vasodilating substances in the renal compartment,
such as renal prostaglandins, i.e. prostaglandin I2 (PGI2) and
prostaglandin E2 (PGE2), but only in an initial phase; the
development of progressive and sustained renal vasocon-
striction leads to the hepatorenal syndrome. Onset of ascites
implies a correct diagnostic tap to identify bacterial fluid
infection [18]. No evidence supports a role for reduced vas-
cular oncotic pressure due to hypoalbuminemia in the patho-
genesis of ascites.
Apart from antioxidant properties, due to the well known
thiol groups enrichment of the molecule, which represents up
to 80% of extracellular thiols, human albumin molecule has
the capacity to bind an extraordinarily diverse range of
molecules. This is possible because the negative charge of
human serum albumin (HSA) facilitates electrostatic binding
of many substances, acting as a storage and vehicle for many
compounds. Furthermore, human albumin exerts a huge driv-
ing force for colloidal osmotic pressure and may directly
influence vascular integrity and permeability by way of in-
teractions with the extracellular matrix [19].
It is well know that albumin deficiency in decompensated
liver cirrhosis is much more pronounced in respect to human
albumin levels detected in plasma, especially in acute on
chronic liver failure (ACLF): actually, effective albumin
concentration in cirrhosis patients is several fold less than the
actual HSA concentration and further reduced in ACLF.
Recent Advancements in Diagnosis and Therapy of Liver Cirrhosis Current Drug Targets, 2016, Vol. 17, No. 12 3

Fig. (1). Liver cirrhosis on needle biopsy or surgical specimens. A-Masson’s trichrome stain of needle biopsy of liver cirrhosis shows typical
diffuse angioarchitectural modifications of hepatic structure and contemporary vascular derangements within either liver cirrhotic nodules and
particularly the surrounding huge fibrous septa spanning the width of the needle core and connecting portal tracts each other (periportal and
centrilobular areas). B-Particular stain of reticular component in liver cirrhosis of needle biopsy. This staining reveals the huge connective
component of the liver cirrhotic altered angioarchitecture. C-Hematoxylin and eosin (H&E) stained surgical resection (from different areas of
the liver) demonstrating diffuse remodeling of hepatic architecture and abnormal vascular relationships at low power. Fibrotic septa of vary-
ing widths divide the hepatic parenchyma into nodules. Several hepatic nodules have vascular structures that may or may not represent termi-
nal hepatic venules; however, they are not normal as they either “adhere” or are too far away from the portal tract/septa. Absence of central
veins is seen in other nodules in this surgical specimen. Note the presence, in the contest of regenerative nodules and fibrotic septa, of an area
of altered hepatocytes with moderate degree of differentiation constituting a structure resembling a regenerative nodule, but represented by
highly dysplastic cells (hepatocellular carcinoma) within the cirrhotic liver. These cells are irregular in shape and exhibit abnormal nuclei
with prominent nucleoli. Note that the nodule has a heterogenous content with area of distinct appearance and central areas with diffuse phe-
nomena of necrosis and degeneration.

Fig. (2). Liver cirrhosis on needle biopsy or surgical specimens. D - Sirius Red stain of septal fibrosis. A huge proliferation of connective
structures are present within the septal area. Vascular involvement is seen and contributes to maintain these structures (active septa). E – Sep-
tal fibrosis: stain the reticular component. Abundant reticulin fibers are well stained in this needle biopsy specimen. Fibrous septa are present
within the portal space (periportal fibrosis) and bridging septa are spreading from the portal tracts to the others and to the central areas of the
liver lobules (pericentral fibrosis and portal-central fibrosis). These angioarchitectural alterations are the hallmarks of the ongoing liver cir-
rhosis. F – Liver cirrhosis and hepatocellular carcinoma: surgical resection. One of the most common appearance of HCC within a cirrhotic
liver is represented by a multinodular entity resembling cirrhotic nodules. Frequently, a distinct nodule of varying size appears in this contest,
which increases in size as it evolves and is frequently associated with the growth of satellite foci in the vicinity of the main tumor, together
with contemporary portal vein invasion. This last phenomenon increases parallel as the disease evolves. Note the presence of a connectival
structure around the nodule (thin fibrous capsule).
4 Current Drug Targets, 2016, Vol. 17, No. 12
CLINICAL MANIFESTATIONS
Clinical signs, laboratory parameters and other findings
may reveal the presence of liver cirrhosis: i.e., cutaneous
signs of cirrhosis, a firm liver on palpation, other comorbid-
ities such as metabolic syndrome, prolonged ethanol intake,
or exposure to hepatotoxic substances. Some clinical mani-
festations are represented by anorexia, body weight loss,
weakness, fatigue, jaundice, pruritus, spider angiomata, gy-
necomastia, increased abdominal girth due to ascites, sple-
nomegaly, palmar erythema, signs of upper gastrointestinal
bleeding, asterixis and confusion, usually accompanied by
sleep disturbances, due to hepatic encephalopathy, digital
clubbing (not only a sign for increased suspicion for a prob-
able sign of the hepatopulmonary syndrome), even if digital
clubbing is a non-specific finding. In fact it can be present in
multiple chronic conditions such as congestive heart failure,
cystic fibrosis, chronic liver disease, inflammatory bowel
disease. The hepatopulmonary syndrome (HPS) is character-
ized by abnormal pulmonary vasodilation and right-to-left
shunting resulting in gas exchange abnormalities, whereas
portopulmonary hypertension is caused by pulmonary artery
vasoconstriction leading to hemodynamic failure. Usually,
there is a gravitational increase in blood flow through dilated
vessels in the lung bases [20], especially when accompanied
by platypnea and orthodeoxia. Some other clinical signs of
liver cirrhosis are parotid gland enlargement and the onset of
the so-called “foetor hepaticus”. The latter is usually caused
by increased portal hypertension and portal-systemic shunt-
ing (usually due to an increased release of dimethyl sulfide)
[21]. Spider angiomata are vascular lesions made up of a
central arteriole surrounded by some other small vessels;
such lesions may occur on the body’s trunk, chest, face or
upper limbs. Male suffering from liver cirrhosis may have
hypogonadism, together with impotence, infertility, loss of
libido and testicular atrophy. In some cases, both follicle-
stimulating hormone (FSH) and luteinizing hormone (LH)
are increased [22]. Females often develop anovulation, am-
erorrhea or irregular menstrual bleeding [23, 24]. Increased
production of androstenedione from adrenal glands together
with increased conversion from androstenedione to estrone
and estradiol contribute to the onset of gynecomastia, with
discomfort in men. These phenomena are frequently associ-
ated with other signs of feminilization, such as the loss of
chest or axillary hair or inversion of the normal male pubic
hair pattern [25]. In short, typical symptoms of liver cirrhosis
include: cutaneous signs of liver disease, a firm liver on pal-
pation, some risk constellations, such as a metabolic syn-
drome, heavy alcohol consumption, exposure to hepatotoxic
substances, and the use of hepatotoxic medications. Cirrhotic
patients with ascites present an elevated risk for the devel-
opment of major complications, such as refractory ascites
and hepatorenal syndrome, spontaneous bacterial peritonitis,
hyponatremia and the so called “cirrhotic cardiomyopathy”.
DIAGNOSIS
Instrumental Diagnosis
Esophagogastroduodenoscopy (EGD) is the hallmark for
the diagnosis of gastroesophageal varices and their bleeding
risk. Imaging techniques (ultrasound, CT, NMR, etc.) often
reveal the disease. Transient elastography, or Fibroscan®, a
Romanelli and Stasi
method recently used for measuring liver stiffness, gives
high values of liver stiffness (the mean optimal cut-off point
of liver stiffness for cirrhosis was 15±4.1 kPa – median 14.5
– values ranged from 9.0-26.5 kPa) [26], while the ultra-
sound reveals an inhomogeneity of the hepatic tissue, an
irregular liver surface, caudate and left lobes enlargement.
Transient elastography and the acoustic radiation force im-
pulse (ARFI) technique can play a pivotal role in the study of
liver fibrosis [26, 27]. Furthermore, portal hypertension leads
to the enlargement of the elastic spleen components and con-
sequent splenomegaly. Physicians should also monitor their
patients for early screening of liver cirrhosis by means of
transient elastography (Fibroscan), if available. Liver stiff-
ness expressed in kPa is particularly useful for confirming
existing liver cirrhosis or for excluding it. Recently, some
studies [28, 29] have evaluated the utility of transient elasto-
graphy for the assessment of short- and long-term longitudi-
nal changes in liver fibrosis in patients with chronic HCV
infection undergoing antiviral treatment. The results of these
researches showed that this method can also detect longitu-
dinal variation in liver fibrosis. Notwithstanding, it is manda-
tory to remember that for the most part the non-invasive
methods cannot differentiate accurately between different
stages of liver fibrosis; they might show if it is present or not
or if overt liver cirrhosis is present, but they cannot show
between stage I or II or I and III accurately. Liver biopsy still
remains the gold standard and still required for proper diag-
nosis. In some cases, Non-invasive tests could not substitute
liver biopsy but can be used to follow up patients already
biopsied.
Liver biopsy is still needed, especially when histological
sample analysis and some specific tissue stains of the tissue
may be of help in differential diagnosis and in confirm the
etiology of the disease (Table 1). Transjugular liver biopsy
gives more information, especially if performed with the aim
of getting further details (“one shot-one shop”: liver biopsy,
measurement of portal pressure through HVPG determina-
tion, transjugular intrahepatic portosystemic shunt (TIPS)
through the suprahepatic veins and the portal collaterals)
[30].
Cirrhotic cardiomyopathy, frequently observed in ad-
vanced phase of the disease, is represented by a chronic car-
diac dysfunction with impaired contractile responsiveness to
stress and/or altered diastolic relaxation (diastolic dysfunc-
tion) with electrophysiological abnormalities in the absence
of other known cardiac diseases, which is much more diag-
nosed not only through the increased plasma levels of pro-
brain natriuretic peptide, but also by challenging patients
with exercise and the consequent demonstration of QT adap-
tation, such as patients studied by us in a recent observation
[31].
Assessment of Advanced Fibrosis/cirrhosis
The accurate assessment of the degree of hepatic fibrosis
also plays a critical role in guiding the diagnosis, treatment
and prognostic assessment in liver cirrhosis, taking into ac-
count the different phases of liver cirrhosis. Liver biopsy is
currently the most reliable method to evaluate the severity of
hepatic fibrosis. However, liver biopsy is an invasive proce-
dure with several limitations in patients with decompensated
cirrhosis, because it is often accompanied by complications,
Recent Advancements in Diagnosis and Therapy of Liver Cirrhosis Current Drug Targets, 2016, Vol. 17, No. 12 5

Table 1. Most common cause of liver cirrhosis.

• Hepatitis C virus infection

• Hepatitis C virus infection plus alcoholic liver disease

• Hepatitis B virus infection

• Hepatitis B virus infection plus alcoholic liver disease

• Alcoholic liver disease

• Cryptogenic causes(*)

(*)Many cryptogenic cases are due to NALFD

• Miscellaneous:

Autoimmune hepatitis

PBC (primary biliary cholangitis)

Secondary biliary cirrhosis (eventually associated with chronic extrahepatic bile duct obstruction)

PSC (primary sclerosing cholangitis)

Hemochromatosis

Alpha-1-antitrypsin deficiency

Granulomatous disease, such as sarcoidosis

Type IV glycogen storage disease

Drug-induced liver disease (amiodarone, methotrexate. etc.)

Venous outflow obstruction (i.e., Budd-Chiari syndrome, VOD, veno-occlusive disease)

Chronic right-sided heart failure

Tricuspid regurgitation

such as ascites, prolonged clotting time and infections. A re-
cent study [32] determined the collagene proportionate area
(CPA) of resected liver tissue samples from patients with
HBV-related decompensated cirrhosis using digital image
analysis, and analyzed the relationship between the CPA and
liver functional reserve in fifty-three resected liver tissue sam-
ples from liver transplant patients with chronic hepatitis B-
induced decompensated cirrhosis. In this study, the CPA of
liver tissue was as low as 11.24% in some patients. The pa-
tients with lower CPAs had mainly macronodular cirrhosis,
and liver transplants were performed mainly due to severe
portal hypertension (gastrointestinal bleeding) even though
their liver functional reserve is still at the compensated stage.
Since, the number of hepatocytes decreases with increasing
number of fibers and CPA value, this study demonstrated a
strong correlation between MELD score, serum total bilirubin
level, INR and CPA and showed significant differences
among three CPA groups (<0.22, 0.22-0.48 and >0.48).
Recently, serum markers have been studied as possible
tools for making non-invasive diagnosis of fibrosis stage,
and for indicating the determination of the stage of the dis-
ease itself. Recently, Tsochatzis et al. [33] compared the
performance of histological semi-quantitative and quantita-
tive methods specifically developed for sub-classifying cir-
rhosis with CPA in patients with alcoholic liver disease,
HCV, HBV nonalcoholic steatohepatitis, autoimmune hepa-
titis. They found that CPA accurately sub-classified cirrhosis
and it is the only independent predictor of clinical decom-
pensation among the other histological systems described to
date.
Non-invasive serum markers may also be used for mak-
ing an accurate prognosis (Table 2). There is a clinical need
for non-invasive measurement of liver fibrosis to diagnose
significant hepatic fibrosis and also to monitor the effects of
antiviral or antifibrotic therapy. Serum levels of different
fibrotic markers have been studied in the past: type IV colla-
gen, hyaluronic acid, laminin, collagen VI, transforming
growth factor beta 1 (TGF β1) and metalloproteinases
(MMPs) or tissue inhibitors of metalloproteinases (TIMPs).
These serum markers have been compared with semi-
quantitative measurements (Table 3), i.e., the METAVIR
scoring-system [44]. Assessment of liver fibrosis by means
of multiple serum markers used in combination is sensitive,
specific, and reproducible. This means that they may be used
together with liver biopsy or with other non-invasive meth-
ods to assess a wide range of chronic liver diseases [for ex-
tensive review see 45-47]. Information given by these mark-
ers must always be considered in the light of the relative
clinical findings [48]. Even through non-invasive biomarkers
of liver fibrosis represent a vital area of research aiming at
improving patient care and disease stratification, and at de-
veloping future antifibrotic therapies. All such tests should
only be used and verified on patients having a definite etio-
logical diagnosis of liver disease.
6 Current Drug Targets, 2016, Vol. 17, No. 12 Romanelli and Stasi

Table 2. Some non invasive markers in CLD.

Extensive Fibrosis or Cirrhosis

No.
Age PLT AST ALT Other Sensitivity PPV NPV
Items Cut-off Specificity
(%) (%) (%)

Age-platelet
2 * * - - - >6 35.9 85.6 10.8 96.5
index [34]

AST-ALT [34] 2 - - * * - >1 38.5 71.5 6.1 96

APRI [35] 2 - * * - - 2 65 95

hyaluronic acid -
ELF score */- N-propept. type II
3 or 4 - - - >9.30 79.1 90.8 75.6 92.3
[36] # collagen – TIMP1
levels

FIB 4 [37] 4 * * * * - >3.25 59.2 82.3 64 79.2

serum albumin
Fibronectin >415
4 - * * - levels – Fi- 60 58 59 44
[38] mg/dl
bronectin levels

α2 macroglobulin
– haptoglobin -
apolipoprotein A-1
FibroTest – γGT - total bili-
7 * - - - 0.8 38 97 92 62
[39] rubin (gamma-
globulin in origi-
nal version) levels
– sex

γGT - cholesterol
Forns [40] 4 * * - - >6.90 41.9 92.9 85.7 61.2
levels

GUCI [41] 3 - * * - prothrombin index 1 80 78 31 97

α2 macroglobulin
Hepascore – γGT - hyaluronic
6 * - - - >0.87 33 92 81.1 56.7
[40] acid - bilirubin
levels - sex

King’s score
4 * * * - INR >16.7 69.2 73.8 11.4 98
[34]

Lok
4 - * * * INR >0.5 94.9 18.1 7.8 96.5
[34]

MP3 score MMP-1 - PIIIP

2 - - - - >0.50 18.7 98.9 94.4 54.0
[40] levels

Pohl index
3 - * * * - 1 50.0 94.3 63.6 90.4
[42]

INR - right hepatic

Sabadell lobe atrophy -
NIHCED 8 * * * * splenomegaly - >6 72 75 81 63.7
[43] caudate lobe hy-
perthrophy

The consequences of decompensated cirrhosis are throm-
bocytopenia due to splenomegaly, loss of hepatic function
and impaired specific hepatic molecule synthesis (albumin,
prothrombin and cholinesterase), together with an altered
detoxifying function, revealed by increased levels of cho-
lestatic indexes, such as gamma-glutamyltranpeptidase (γ-
GT) and alkaline phosphatase, together with total bilirubin.
Cytolytic markers (alanine aminotransferase –AST- and as-
partate aminotransferase –ALT-) are often within the normal
range or slightly higher [48]. Some patients with liver cirrho-
sis may have severe muscle cramps [49, 50] and possibly this
may be due to a reduction in circulating plasma volume.
Recent Advancements in Diagnosis and Therapy of Liver Cirrhosis
In the absence of a clear diagnosis of liver cirrhosis, con-
temporary determinations of serum and ascitic albumin con-
centrations are useful for the determination of serum albu-
min ascites gradient. When this gradient is > 1.1 g/dL, a con-
ceivable diagnosis of portal hypertension is obtainable [51].
Table 3. Score of liver fibrosis according to METAVIR score
[44].
No fibrosis
Stellate enlargement of portal tract but without septa formation
Enlargement of portal tract with rare septa formation
Numerous septa formation
Cirrhosis
NATURAL COURSE
A lower survival rate in liver cirrhosis was first showed
by study from Spain, who observed that the onset of ascites,
and varices, together with the progression of portal hyperten-
sion, markedly increase mortality rate [52]. Subsequent stud-
ies have confirmed that the onset of “decompensation” (i.e.,
ascites, bleeding, infections, and hepatic encephalopathy)
determines a 50% decrease in survival in 2 years of follow-
up [1, 52]. When there are no varices, the “compensated”
stage of the disease, is characterized by a less than 10% mor-
tality rate [1]. According to D’Amico et al. [1], it is possible
to identify different phases of liver cirrhosis, each character-
ized by its own risk of cumulative mortality rate. The first
phase consists in compensated liver cirrhosis without
varices, which has a calculated mortality rate of 1%/year.
The second phase is characterized by esophageal varices and
has a mortality rate of 3-4%/year. The third phase is charac-
terized by the presence of ascites, with a 20% mortality
rate/year. The fourth is characterized by bleeding from gas-
trointestinal varices and has 57% mortality rate/year. The last
phase is characterized by further complications of liver cir-
rhosis (spontaneous bacterial peritonitis and other infections,
kidney failure, hepatic failure and jaundice), which raise the
cumulative calculated mortality risk to 67%/year [1, 53].
Acute decompensating events leading to organ failure have a
30% mortality rate, which is higher in patients with no pre-
vious complications [54]. At present, some predictive scores
are used to improve prognosis accuracy. The histological
aspects of liver cirrhosis are of no help in measuring disease
progression, because they are static and therefore useless
once the cirrhotic stage has been reached. Collagen propor-
tionate area (CPA) determinations, together with portal pres-
sure measurements (HVPG determination), may add some
useful information and offer some valid help in making dis-
ease prognosis [55]. As previously mentioned, non-invasive
tests for liver cirrhosis might be valid alternatives to liver
biopsy [56]. Some of them, such as Fibrotest, Hepascore,
AST to Platelet Ratio Index (APRI) and Enhanced Liver
Fibrosis (EFL), are frequently used as prognostic markers
and well-established methods for the staging of fibrosis in
various liver diseases. These tests, together with Fibroscan®
(transient elastography), give a better prediction of the natu-
ral course of the disease [46, 57, 58]. When the decompen-
Current Drug Targets, 2016, Vol. 17, No. 12 7
sated disease is associated with major complications (ascites,
gastrointestinal bleeding, hepatic failure, jaundice and hepa-
tocellular carcinoma), the Child-Pugh score, the MELD
score, or the UKELD score, are useful. They explore some of
the principal clinical and laboratory markers of the disease
itself, such as hepatic encephalopathy, peritoneal fluid accu-
mulation, serum albumin concentration, prothrombin (INR)
time, serum bilirubin levels, serum sodium concentration,
and serum creatinine levels [59, 60].
The hepatopulmonary syndrome (HPS), characterized by
0
defects in oxygenation due to pulmonary abnormalities, is
1 associated with advanced liver disease and occurs in 10-32%
of cirrhotic patients. Dyspnea and hypoxemia can be severe
2 and often worsen in the upright position. Gross dilatation of
3 the precapillary and capillary vessels occurs with ventila-
tion–perfusion mismatch. The syndrome usually improves
4 after liver transplantation [61, 62]. The disease progression is
shown in (Fig. 3).
PREVENTION AND TREATMENT OF COMPLICA-
TIONS
Since liver cirrhosis is the end stage of CLD, the course
of the disease itself can progress for many years and even
decades. Therefore, liver cirrhosis prevention is made by
screening programs that detect increments in AST/ALT/
gamma-GT serum levels, or exploration of indices for
NAFLD (age, platelet count, serum albumin concentration
and glucose tolerance tests), routine upper abdominal ultra-
sonography or transient elastography (Fibroscan®). These
methods could be useful for assessing liver disease and its
natural course, however prevention should be focused on
early detection and treatment of the underlying cause of liver
disease to prevent progression, because it is important to
outline that liver enzymes are not reflective of liver health,
since patients with advance cirrhosis can have liver enzyme
plasma levels within the normal range.
TREATMENT
Specific treatment is required to prevent fibrosis and fur-
ther deterioration of liver function. It consists in eliminating
the underlying causes of the disease. For example, CLD due
to copper accumulation (Wilson’s disease) improves in re-
sponse to copper chelating agents use. Venesection gives
amelioration in genetic hemochromatosis (C282Y or H63D
positivity in homo- or heterozygosis) and the use of steroids
and immunosoppressant agents halts the deterioration of
autoimmune hepatitis. Abstinence is mandatory in alcoholic
liver disease. Antiviral treatment could be used for all vire-
mic patients with CLD (either HBV or HCV positive sub-
jects), in order to obtain viral clearance. HCV treatments are
rapidly evolving, and several drugs are in various stages of
development. These new molecules are able to treat more
than 90% of HCV-infected patients and are effective against
genotypes that were previously difficult to treat [63]. Several
longitudinal studies have shown that a sustained virological
response is associated with fibrosis regression [64, 65].
Moreover, these new drugs may be not only effective in
terms of biochemical and virological responses, but also in
reconverting clinically decompensated cirrhosis to compen-
sated one [66]. Treatment of HBV or HCV infections with
8 Current Drug Targets, 2016, Vol. 17, No. 12
Fig. (3). Progression of liver cirrhosis [1, 53].
antiviral agents has been associated with liver histological
improvements. The administration of adefovir and entecavir
in HBV infections has determined a histological improve-
ment over a period of 240 weeks [67]. The nucleo-
side/nucleotide analogs cause viral suppression of over 99%,
the regression of fibrosis. The disadvantages include the un-
limited duration of treatment, the low rate of loss of HBsAg
and the seroconversion to anti-HBs. Treatment with teno-
fovir for 5 years resulted in liver fibrosis regression in cir-
rhotic patients [68]. In a study similar to the previous ones,
entecavir treated patients showed similar results in terms of
histological amelioration [69].
Lifestyle modifications ameliorate citolytic indices and
improve hepatic steatosis, monitored either with ultrasound
[70, 71] or other techniques [72]. NAFLD is negatively in-
fluenced by the contemporary presence of other typical
symptoms of metabolic syndrome, such as obesity (increased
abdominal girth, together with Body Mass Index (BMI) /
Body Surface Area (BSA) (Du Bois) index greater than 30)
or insulin resistance/type 2 diabetes mellitus. Metabolic syn-
drome is usually associated with more severe fibrosis and
cirrhosis in chronic liver disease [73]. Many studies have
recently confirmed the significant reduction in liver fat by an
average of 40-50%, proportional to the intensity of the life-
style intervention, generally requiring a body weight loss of
5-10% [74]. Evidence for weight loss as a means to improve
liver histology in NASH comes from a study of NASH obese
subjects with lifestyle modifications (such as behavior modi-
fication, diet and physical activity for 48 weeks, 200 min-
Romanelli and Stasi
utes/week) versus structured basic education alone. Patients
undergoing lifestyle interventions registered almost a 10%
weigh loss reduction together with improvements in steato-
sis, necrosis, lobular inflammation, ballooning, and NAFLD
activity score (NAS) [75].
Obesity (BMI>30 in the Caucasian subjects) represents
an independent predictive factor of cirrhosis in patients with
alcoholic liver disease [76]. Berzigotti et al. studied obesity
such as an independent factor in the development clinical
decompensation during the long course of liver cirrhosis and
found an association with HVPG determination and plasma
albumin levels [77].
Treatment of primary biliary cholangitis aimed at slow-
ing the disease and prolonging life include ursodeoxycholic
acid. Immunosuppressant drugs have been widely used, but
their effectiveness should be confirmed. Biliary obstructions
and secondary liver cirrhosis may benefit from biliary de-
compression [78-80].
Portal Hypertension Varices and Bleeding
Portal hypertension is the necessary hallmark for the
presence of complications in liver cirrhosis and determines a
higher morbidity and mortality rate of the disease. Hepatic
vein catheterization and the measurement of the hepatic ve-
nous pressure gradient (HVPG) is the current standard tech-
nique for defining portal pressure. It plays a pivotal role in
determining the portal pressure levels at which the risk of
bleeding is high. Measuring portal pressure by means of
Recent Advancements in Diagnosis and Therapy of Liver Cirrhosis
HVPG is a relatively new approach and is an accurate prog-
nostic indicator [81]. A valid diagnostic tool may result by
the use of various non-invasive methods together with an
invasive determination of HVPG. Thus far, liver stiffness
measurement (LSM) obtained by transient elastography is
the most promising approach for monitoring fibrosis pro-
gression caused by the worsening of portal hypertension.
LSM has been demonstrated to have a good correlation with
HVPG value, especially below a cut-off values of 10-12
mmHg. This indicates that LSM is helpful in detecting clini-
cally significant portal hypertension and an increased risk of
bleeding from the gastrointestinal tract [82]. According to
these data and some other studies the risk of developing gas-
trointestinal varices is about 5-10% per year [83], while the
risk of first variceal bleeding is 12% per year [84]. Variceal
bleeding has a high mortality rate from 20-30% to 57% [1,
53], [85, 86]. Since the majority of untreated patients have a
high risk of further complications (recurrent variceal bleed-
ing, liver failure, hepatic encephalopathy, refractory ascites
and increased susceptibility to infections) and a poor progno-
sis within this first year after the initial episode of bleeding,
the prevention of variceal bleeding is mandatory. Therapeu-
tic measures include the use of non-selective beta-blockers,
in order to lower portal pressure via a reduction of cardiac
output and increase in splanchnic vascular resistance, and
endoscopic band ligation. Beta-blockers (usually propranolol
or carvedilol) are used for small varices; varices with a di-
ameter over 5 mm should be treated either with beta-blockers
or endoscopic ligation. These drugs and procedures decrease
the risk of gastrointestinal hemorrhage by 20-40%, according
to various clinical studies [87]. Since HVPG is an invasive
method for measuring portal hypertension, beta-blocker effi-
cacy can be monitored by the titration of the dose up to the
maximum level tolerated, aiming at a heart rate below 60
bpm [82-84].
Some factors associated with early failure (within one
week) include active bleeding at index endoscopy, severity
of bleeding, severity of liver disease and portal hypertension,
and evidence of liver injury [86, 87]. Factors associated with
an increased risk of rebleeding during the first 1-2 months in
patients with alcohol-induced cirrhosis include severity of
the first bleeding, severity of portal hypertension, the pres-
ence of decompensated cirrhosis (ascites) and a plasma bili-
rubin above 3.0 mg/dL [87, 88]. A reduction of the HVPG to
less than 12 mmHg, or by at least 20%, reduces the risk of
rebleeding from 60% to 0-13% [87, 88]. Acute variceal
bleeding, treated with terlipressin or octreotide plus antibiot-
ics and eventually endoscopic band ligation of varices, or
endoscopic sclerotherapy, is currently most frequently
treated by inserting TIPS, especially in the first 72 hours
after the onset of hemorrhage [89-91]. This procedure avoids
the risks involved in general anesthesia and major surgery.
The portal vein decompression and the consequent decrease
in portal hypertension make it similar to surgical portacaval
shunts and is especially useful in Child-Pugh A or B class
patients. These patients can benefit from TIPS insertion be-
cause they have recurrent variceal hemorrhage despite com-
bined pharmacologic and endoscopic treatment. It is of vital
importance, however, that transplant candidates are referred
to a transplant center as soon as possible. Early treatment of
acute hemorrhage with vasoactive drugs and antibiotics can
Current Drug Targets, 2016, Vol. 17, No. 12 9
avoid endoscopy and lower the risk of infections. It also
lowers the consequent risk of further decompensation and a
higher mortality rate [90, 91]. TIPS insertion is useful in
both the treatment of acute variceal bleeding within the first
72 hours and in the prevention of recurrent hemorrhage. This
phenomenon, during the first year after successful treatment
of acute variceal bleeding, frequently occurs in up to 60 to
80% of cases, especially if not initially treated with TIPS
insertion [86]. Standard of care in variceal rebleeding pre-
vention is currently a combined treatment of a non selective
beta-blocker and either band ligation or sclerotherapy (less
used). This standard treatment can lower hemorrhagic risk
from 70% to 20-30% [92-94]. The failure of medical therapy
is overcome by TIPS insertion or surgical shunt [95]. It is
important to note that hepatic encephalopathy is a common
complication of TIPS insertion and occurs at least twice
more frequently after this procedure according to most stud-
ies. Risk factors for its development are age, liver failure,
shunt diameter and history of encephalopathy prior to TIPS
[96].
Ascites
More than 60% of the patients affected by compensated
cirrhosis eventually develop ascites, usually within 10 years.
In turn, this complication causes other complications, such as
spontaneous bacterial peritonitis, hyponatremia, hepatorenal
syndrome, and hepatic hydrothorax. Moreover, ascites fa-
vours the onset of gastrointestinal bleeding, pulmonary
atelectasy, and the formation of abdominal hernias. New
ascites is associated with a 1-year mortality rate of about
20% [97]. Renal failure often accompanies and complicates
advanced liver cirrhosis and has a 50% mortality rate within
the first month [98]. It makes the overall mortality rate seven
times higher. Un-complicated ascites is the first stage of the
disease. Once it is detected through physical examination
and ultrasound tests, the volume of peritoneal fluid indicates
the kind of to be used (as reported by International Ascites
Club – (IAC) -, American Association for the Study of Liver
Diseases (AASLD) and European Association for the Study
of the Liver (EASL) Guidelines). Grade 1, or mild ascites,
grade 2, or discrete ascites and grade 3, or tense ascites, is
the standard definition of ascites. Only patients with grade 2
or 3 ascites can be treated, such as outpatients or inpatients
with dietary sodium restriction and increased renal sodium
excretion caused by diuretics. Bed rest is required since the
upright position activates the sodium/water retaining systems
by impairing the renal functions [99, 100]. This results in a
higher serum aldosterone levels, even at a pre-ascitic stage,
and in a lower glomerular filtration rate, and this increases
renal sodium retention [101]. A negative sodium balance can
be obtained by reducing dietary sodium by about 20%, espe-
cially in patients at their first episode of ascites [102]. The
initial treatment of these patients consists in prescribing a
dietary sodium content of about 60-120 mEq (3-6 g of so-
dium chloride) or 88 mEq Na (2000 mg) per day, including
all foods, liquids and medications, together with diuretics.
These consist in antialdosterone or potassium-sparing (can-
renoate potassium or canrenone, its active metabolite) and
high-ceiling diuretics (furosemide, torasemide) [103]. Die-
tary fluid restriction is limited to the patients who have low
plasma sodium concentrations (below 120 mEq/L), because
10 Current Drug Targets, 2016, Vol. 17, No. 12
this procedure generally makes an already thirsty patient
even more uncomfortable. Bernardi et al. [104] demonstrated
that combo therapy is more effective for patients with recur-
rent ascites than in patient at their first episode of ascites.
Moreover, by including different populations of cirrhotic
patients with ascites, that is, the ones at their first episode of
ascites and the one with diuretic-resistant or refractory as-
cites, there may be discrepancies between the methods of
drug administration used, i.e., aldosterone antagonists with a
stepwise increase every 7 days (100 mg/day), up to 400
mg/day, with furosemide (40 mg/day, up to 160 mg/day),
only added for patients who do not respond to high doses of
antialdosterone drugs or combined therapy. Nonetheless,
combined therapy gives better results than sequential therapy
[105, 106]. According to previous studies and clinical data,
the current European Guidelines advocate sequential treat-
ment for first-case ascites, and combined therapy for recur-
rent ascites [107]. Antialdosterone drugs plus high-ceiling
diuretics should be administered at increasing doses to
achieve a body weight loss of at least 1 Kg per day in pa-
tients with ascites and peripheral edema, and 0.5 Kg per day
in patients having only ascites [108]. Hydro-electrolyte im-
balances are frequently observed in patients treated with high
doses of diuretics, especially with the maximum doses of
400 mg antialdosterone drugs and 160 mg high-ceiling diu-
retics. Such doses are rarely used and may cause various
complications, such as renal failure, hepatic encephalopathy,
electrolyte disorders (hyponatremia and hypo/hyperkalemia),
gynecomastia and muscle cramps. Resistent and refractory
ascites are two more-advanced steps in the natural history of
ascites. During the disease peritoneal fluid gradually be-
comes progressively untreatable or unsusceptible to treat-
ment without the onset of serious collateral side effects
[109]. Large volume paracentesis is reserved to grade 3 as-
cites, together with compensating i.v. human albumin infu-
sion (6-8 g/liter ascitic fluid removed). Recent data show that
the in vivo administration of human albumin solutions to
cirrhotic patients significantly improves the plasma-induced
impairment of macrophage proinflammatory cytokine pro-
duction in vitro. As a result, human albumin solution infu-
sions can be beneficial, as we observed in our clinical expe-
rience, and can be used to reduce circulating PGE2 levels,
attenuating immune suppression and reducing the risk of
infection in patients with acutely decompensated cirrhosis or
ESLD (end stage liver diseases) [110]. According to a re-
cently published meta-analysis of 17 trials involving 1225
patients, albumin infusion after large volume paracentesis
seems to reduce the mortality rate. Albumin infusion is able
to reduce the mortality rate and is recommended therefore
when more than 5 liter of ascitic fluid are removed [111].
The use of albumin is necessary to reduce the onset of para-
centesis-induced circulatory dysfunction (PICD). In this
study population, some authors demonstrated that non-
selective beta-blockers, such as propranolol, give poor re-
sults, especially in the case of paracentesis-induced circula-
tory dysfunction [112, 113]. At a starting dose of 7.5 mg
thrice a day oral midodrine has been shown to increase daily
urinary volume, urinary sodium excretion and average arte-
rial pressure. It also improves systemic hemodynamics and
the survival rate of patients with recurrent/refractory ascites.
This drug may convert refractory ascites back to a diuretic-
sensitive one [114]. As compared to diuretic treatment alone,
Romanelli and Stasi
hospital stay is significantly reduced, as are all severe side-
effects, thanks to large volume paracenteses plus i.v. human
albumin infusion [107]. On the other hand survival rate has
proven to be significantly lower both in the meta-analysis
previously mentioned and in one study coming by our local
group. In our randomized, unblinded trial on one hundred
patients, long-term human albumin i.v. infusion increased
patient survival and reduced the risk of ascites recurrence
[115]. Further studies are currently being made on this topic
to investigate this first observation [116]. A recently discov-
ered drug family in the treatment of ascites consists in vap-
tans, which are selective antagonists of the V2-receptors of
vasopressin. A large randomized trial with vaptans, including
patients with cirrhosis did not demonstrate any clinical bene-
fits in cases of long-term ascites and then seemed to be an
increase in the mortality rate [117]. TIPS implantation is an
alternative approach to these patients with respect to ortho-
topic liver transplantation and it has proven to be useful,
especially in subjects with a preserved liver function [118].
Cirrhotic patients with ascites are particularly sensitive to
non-steroidal anti-inflammatory drugs (NSAIDs), such as
indomethacin, ibuprofen, aspirin, and sulindac. These can
cause a further decrease in renal sodium excretion, urinary
flow dilution, and renal function due to altered renal prosta-
glandin synthesis. Furthermore, hyponatremia, diuretic resis-
tance and acute renal failure may suddenly appear in these
patients, once they have been exposed to these drugs [119,
120]. Angiotensin converting enzyme inhibitors, even at low
doses, should be avoided in patients with cirrhosis and as-
cites due to the onset of arterial hypotension and the devel-
opment of an impaired renal function [121, 122]. According
to the IAC definition, the hepatorenal syndrome is a rare, but
severe complication of ascites and is characterized by func-
tional acute renal dysfunction typical of cirrhotic patients
with ascites and liver failure (and even more in cases of
acute liver failure and alcoholic hepatitis). This syndrome
consists in renal failure, profound systemic hemodynamic
and cardiac alterations, together with major endogenous
vasoactive system hyperactivity in the absence of any other
known causes of renal failure [108, 123]. Type 2 hepatorenal
syndrome has a less severe prognosis, with a slight increase
in creatininemia (between 1.5 and 2.5 mg/dL) and BUN and
quite a stable level during a few days or weeks. Over a
longer period of time, it increases slowly. It is characterized
by circulatory dysfunction and a pronounced peripheral
splanchnic vasodilation, associated with refractory ascites
and marker sodium and water retention. Viceversa, type 1
hepatorenal syndrome is a severe condition, characterized by
a progressive and significant increase in renal function in-
dexes only over a few days (> 2.5 mg/dL in two weeks), and
it more frequently ends in death. Frequently, terminal renal
failure is accompanied by precipitating events, such as spon-
taneous bacterial peritonitis. It is conceivable that efficacious
prevention of spontaneous bacterial peritonitis through cor-
rect diagnosis and appropriate treatment can prevent the on-
set of type 1 hepatorenal syndrome. At present, orthotopic
liver transplantation remains the only effective treatment of
type 1 hepatorenal syndrome. In the last few years, mi-
dodrine, terlipressin and octreotide, accompanied by human
albumin infusion or noradrenaline therapy, have proven to be
partially effective in the treatment of this syndrome [124].
Recent data, provided by a multicenter study group seem to
Recent Advancements in Diagnosis and Therapy of Liver Cirrhosis
favour terlipressin plus albumin infusion treatment compared
to other therapeutic procedures [125]. Nowadays, TIPS in-
sertion seems to be particularly effective in patients having
increased values of portal hypertension because it is able to
increase urinary Na volume by about 100 mEq/day at 1 year
post-TIPS [126]. When patients are kept down to a low-
sodium dietary content for 6-12 months and assume diuretics
to avoid fluid retention, further ascites resolution can occur
up to 12 months post-TIPS, with almost 80% of patients re-
sponding with complete disappearance of ascites. These re-
sults evidence an improvement in renal function, a better
nutritional state and a positive nitrogen balance with a better
life quality [127]. TIPS has proven useful for both refractory
ascites patients and recurrent gastrointestinal hemorrhagic
patients with severe portal hypertension. Nonetheless, it is
necessary to perform some preliminary pre-TIPS procedures,
such as transthoracic contrast-enhanced echocardiography
and Doppler to explore the eventual presence of a patent
foramen ovale (PFO), which would increase the risk of
ischemic lesions of the brain, as recently demonstrated by
our study group [128].
Encephalopathy
Hepatic encephalopathy (HE) is one of the most debilitat-
ing complications of liver disease. Advanced liver disease
and portosystemic shunting have well-known consequences
on the body and brain functioning. Alterations in brain func-
tioning, which can produce behavioral, cognitive, and motor
effects, were termed portosystemic encephalopathy, and later
included in the term HE [129]. The prevalence of this disor-
der at the time of diagnosis of cirrhosis is usually 10-14%
[130]. This complication is usually associated with poor sur-
vival rate and a high risk of recurrence [131] since the mor-
tality rate goes up to 64% [132]. Precipitating events of HE
commonly consist in constipation, dehydration, infec-
tion/sepsis, over-aggressive therapy with diuretics/sedatives,
or gastrointestinal bleeding. In patients with liver cirrhosis,
overt HE is often associated with the decompensated phase
of the disease, such as variceal bleeding or ascites [133].
Treatment of HE is mandatory immediately after checking
precipitating factors, because nearly 90% of the patients can
be treated just by eliminating the precipitating factors [134].
Lactulose, a non absorbable disaccharide, is preferred in the
treatment of recurrent HE. Through a randomized clinical
trial, Sharma et al. [135] demonstrated, a 27% lower risk of
recurrence compared to placebo. This drug is usually admin-
istered at a starting dose of 25 mL of syrup every 12 h, and
then increased until at least two soft or loose bowel move-
ments per day are produced. Overaggressive use of the drug
leads to aspiration, dehydratation, hypernatremia or severe
skin irritation [136]. Rifaximin has been used extensively in
the treatment of HE as reported by various authors [137]. It
is equivalent or superior to all comparable agents, and has an
excellent tolerability. Bass et al. reported that, lactulose and
neomycin had an equivalent capability in cognitive im-
provement and ammonia lowering [138]. Rifaximin and lac-
tulose together are effective in the treatment of HE and re-
duce the recurrence risk by about 25%. Furthermore, rifaxi-
min plus daily i.v. human albumin administration have
proven to afford better post-discharge survival [139]. This
molecule has also clearly proven to improve patient’s health-
Current Drug Targets, 2016, Vol. 17, No. 12 11
related life quality and enhance driving skills, especially
when patients are affected by both overt HE and the so-
called minimal HE [140]. L-ornithine L-aspartate (LOLA),
by i.v. (and not oral administration), has improved patients’
ability in psychometric testing and post-prandial plasma ve-
nous ammonia levels [141]. Other molecules are currently
under study in the treatment of this syndrome, i.e., OCR-002
(ornithine phenylacetate) in the form of the phenylacetate
salt of L-ornithine, capable of stimulating glutamine produc-
tion, glutamine conjugation and urinary excretion [142].
Orthotopic Liver Transplantation
Orthotopic liver transplantation is the most radical and
effective treatment for patients having end-stage liver disease
and some of its complications, including hepatocellular car-
cinoma.
Future
Further research is needed in the field of liver cirrhosis,
especially for determining the most cost-effective strategies.
Few, new protease inhibitors and some other proteases are
promising drugs, but they are only at the preliminary stage of
study. Beta-blockers in refractory ascites treatment need fur-
ther studies. The hepatorenal syndrome seems to improve
when treated by terlipressin plus human albumin administra-
tion. There are some promising molecules for the treatment
of HE and minimal HE. Large esophageal varices seem to be
best treated by band ligation as primary prophylaxis, but
beta-blocker administration does not seem less effective.
CONFLICTS OF INTEREST
The author(s) confirm that this article content has no con-
flict of interest.
SUPPORTIVE FOUNDATIONS
This paper was partially founded by MIUR (Ministero
Italiano dell’Università e della Ricerca) - Ex-60% Funds;
and by PRIN Co-Financed Project, 2010-2011 - No.
2010C4JJWB_007 6-area, Hepatic Steatosis.
ACKNOWLEDGEMENTS
Many thanks for their kindly support to Prof. Giorgio La
Villa, M.D. and Prof. Giacomo Laffi, M.D. Many thanks for
the slides herein enclosed to Prof. Luca Messerini, M.D.,
Associate Professor of Anatomia Patologica, University of
Florence. We also thank Deborah Bliss for English editing.
REFERENCES
[1] D’Amico G, Garcio-Tsao G, Pagliaro L. Natural history and prog-
nostic indicators of survival in cirrhosis: a systematic review of 118
studies. J Hepatol 2006; 44: 217-31.
[2] Britton RS, Brown KE. Genetic hemochromatosis and Wilson’s
disease: role for oxidant stress? Hepatology 1995; 21: 1195-97.
[3] Camaschella C. Treating iron overload. N Engl J Med 2013; 368:
2325-27.
[4] Deutsch M, Emmanuel T, Koskinas J. Autoimmune hepatitis or
Wilson’s disease: a clinical dilemma. Hepat Mon 2013; 13: e7872.
[5] Wu SJ, Yang YH, Tsuneyama K, et al. Innate immune and primary
biliary cirrhosis: activated invariant natural killer T cells exhacer-
bate murine autoimmune cholangitis and fibrosis. Hepatology
2011; 53: 915-25.
12 Current Drug Targets, 2016, Vol. 17, No. 12
[6] Poupon R, Chazouilleres O, Corpechot C, Chretien Y. Develop-
ment of autoimmune hepatitis in patients with typical autoimmune
hepatitis. Hepatology 2006; 44: 85-90.
[7] Murray CJ, Vos T, Lozano R, et al. Disability-adjusted life years
(DALYs) for 291 diseases and injuries in 21 regions, 1990–2010: a
systematic analysis for the Global Burden of Disease Study 2010.
Lancet. 2012; 380: 2197–223.
[8] Hoyert DL, Xu J. Deaths: preliminary data for 2011. National vital
statistics reports; vol 61, no. 6. Hyattsville, MD; National Center
for Health Statistics, 2011. Available at: URL: http: //
www.cdc.gov/nchs/data/nvst/nvsr61/nvsr61_06.pdf.
[9] Mokdad AA, Lopez AD, Shahraz S, et al. Liver cirrhosis mortality
in 187 countries between 1980 and 2010: a systematic analysis.
BMC Med. 2014 Sep 18; 12: 145 doi: 10.1186/s12916-014-0145-y.
[10] Stasi C, Silvestri C, Voller F, Cipriani F. Epidemiology of Liver
Cirrhosis. J Clin Exp Hepatol. 2015; 5: 272 doi: 10.1016/
j.jceh.2015.06.002.
[11] Innes HA, Hutchinson SJ, Barclay S, et al. Quantifying the fraction
of cirrhosis attributable to alcohol among chronic hepatitis C virus
patients: implications for treatment cost-effectiveness. Hepatology
2013; 57: 451-60.
[12] Lazo M, Hernaez R, Bonekamp S, et al. Non-alcoholic fatty liver
disease and mortality among US adults: prospective cohort study.
BMJ 2011; 343: d6891 doi: 10.1136/bmj.d6891.
[13] Perz JF, Armstrong GL, Farrington LA, Hutin YJ, Bell BP. The
contributions of hepatitis C virus infections to cirrhosis and pri-
mary liver cancer worldwide. J Hepatol 2006; 45: 529-38.
[14] Lozano R, Naghavi M, Foreman K, et al. Global and regional mor-
tality from 235 causes of death for 20 age groups in 1990 and 2010:
a systematic analysis for the Global Burden of Disease Study 2010.
Lancet 2012; 380. 2095-128.
[15] Crawford JM, Burt AD. Anatomy, pathophysiology, and basic
mechanisms of disease. In: Burt AD, Portmann B, Ferrell LD (Eds)
MacSween’s Pathology of the liver, 6th ed, Philadelphia, PA: Chur-
chill Livingstone; 2012: 1-78.
[16] Minano C, Garcia-Tsao G. Clinical pharmacology of portal hyper-
tension. Gastroenterol Clin North Am 2010; 39: 681-95.
[17] Wiest R, Groszmann RJ. The paradox of nitric oxide in cirrhosis
and portal hypertension: too much, not enough. Hepatology 2002;
35: 478-91.
[18] Borzio M, Salerno F, Piantoni L, et al. Bacterial infection in pa-
tients with advanced cirrhosis: a multicentre prospective study. Dig
Liver Dis 2011; 33: 41-8.
[19] Jalan R, Schnurr K, Mookerjee RP, et al. Alterations in the func-
tional capacity of albumin in patients with decompensated cirrhosis
is associated with increased mortality. Hepatology 2009; 50: 555-
64.
[20] Martinez GP, Barbera JA, Visa J, et al. Hepatopulmonary syn-
drome in candidates for liver transplantation. J Hepatol 2001; 34:
651-7.
[21] Tangerman A, Meuwese-Arends MT, Jansen JB. Causes and com-
position of foetor hepaticus. Lancet 1994; 343: 1569.
[22] Van Thiel DH, Gavaler JS, Spero JA, et al. Patterns of hypotha-
lamic-pituitary-gonadal dysfunction in men with liver disease due
to different etiologies. Hepatology 1981; 1: 39-46.
[23] Burra P, Germani G, Masier A, et al. Sexual dysfunction in chronic
liver disease: is liver transplantation an effective cure? Transplanta-
tion 2010; 89: 1425-9.
[24] Cundy TF, Butler J, Pope RM, Saggar-Malik AK, Wheeler MJ,
Williams R. Amenorrhoea in women with non-alcoholic liver dis-
ease. Gut 1991; 32: 202-06.
[25] Van Thiel DH, Gavaler JS, Schade RR. Liver disease and the hypo-
thalamic pituitary gonadal axis. Semin Liver Dis 1985; 5: 35-45.
[26] Tsochatzis EA, Gurusamy KS, Ntaoula S, Cholongitas E, Davidson
BR, Burroughs AK. Elastography for the diagnosis of severity of
fibrosis in chronic liver disease: a meta-analysis of diagnostic
accuracy. J Hepatol 2011; 54: 650-9.
[27] Friedrich-Rust M, Romen D, Vermehren J, et al. Acoustic radiation
force impulse-imaging and transient elastography for non-invasive
assessment of liver fibrosis and steatosis in NAFLD. Eur J Radiol
2012; 81: e325-31.
[28] Stasi C, Arena U, Zignego AL, et al.Longitudinal assessment of
liver stiffness in patients undergoing antiviraltreatment for hepatitis
C. Dig Liver Dis. 2013; 45: 840-3.
Romanelli and Stasi
[29] Martinez SM, Foucher J, Combis JM, et al. Longitudinal liver
stiffness assessment in patients with chronic hepatitis C undergoing
antiviral therapy. PLoS One 2012; 7: e47715
[30] Cholongitas E, Quaglia A, Samonakis D, et al. Transjugular liver
biopsy: how good is it for accurate histological interpretation? Gut
2006; 55: 1789-94.
[31] Barletta G, Del Bene R, Romanelli RG, Marra F, Venditti F, Laffi
G. QT adaptation during exercise in cirrhosis. Am J Cardiol 2016;
in press.
[32] Xie SB, Ma C, Lin CS, Zhang Y, Zhu JY, Ke WM. Collagen
proportionate area of liver tissue determined by digital image
analysis in patients with HBV-related decompensated cirrhosis.
Hepatobiliary Pancreat Dis Int 2011; 10: 497-501.
[33] Tsochatzis E, Bruno S, Isgro G, et al. Collagen proportionate area
is superior to other histological methods for sub-classifying
cirrhosis and determining prognosis. J Hepatol. 2014; 60: 948-54.
[34] Shehab H, Elattar I, Elbaz T, Mohey M, Esmat G. CUFA algo-
rithm: assessment of liver fibrosis using routine laboratory data. J
Viral Hepat 2014; 21: 956-64.
[35] Wai CT, Greenson JK, Fontana RJ, Kalbfleisch JD, Marrero JA,
Conjeevaram HS, et al. A simple noninvasive index can predict
both significant fibrosis and cirrhosis in patients with chronic hepa-
titis C. Hepatology 2003; 38: 518-26.
[36] Catanzaro R, Milazzo M, Arona S, et al. Diagnostic accuracy of
enhanced liver fibrosis test to assess liver fibrosis in patients with
chronic hepatitis C. Hepatobiliary Pancreat Dis Int 2013; 12: 500-
07.
[37] Ahmad W,Ijaz B, Javed FT, et al. A comparison of four fibrosis
indexes in chronic HCV: development of new fibrosis-cirrhosis
index (FCI). BMC Gastroenterol 2011; 11: 44.
[38] Attallah AM, Abdallah SO, Attallah AA, et al. Diagnostic value of
fibronectin discriminant score for predicting liver fibrosis stages in
chronic hepatitis C virus patients. Ann Hepatol 2013; 12: 44-53.
[39] Imbert-Bismut F, Ratziu V, Pieroni L, et al. Biochemical markers
of liver fibrosis in patients with hepatitis C virus infection: a
prospective study. Lancet 2001; 357: 1069-75.
[40] Leroy V, Hilleret MN, Sturm N, et al. Prospective comparison of
six non-invasive scores for the diagnosis of liver fibrosis in chronic
hepatitis C. J Hepatol 2007; 46: 775-82.
[41] Islam S, Antonsson L, Westin J, Lagging M. Cirrhosis in hepatitis
C virus-infected patients can be excluded using an index of stan-
dard biochemical serum markers. Scand J Gastroenterol 2005; 40:
867-72.
[42] Andrés-Otero MJ, De-Blas-Giral I, Puente-Lanzarote JJ, et al.
Multiple approaches to assess fourteen non-invasive serum indexes
for the diagnosis of liver fibrosis inchronic hepatitis C patients.
Clin Biochem 2016; 49: 560-65.
[43] Bejarano G, Vergara M, Dalmau B, et al. Prospective evaluation of
liver fibrosis in chronic viral hepatitis C infection using the
Sabadell NIHCED (Non-Invasive Hepatitis-C-Related Cirrhosis
Early Detection) index. Rev Esp Enferm Dig 2009; 101: 325-35.
[44] Bedossa P, Poynard T. An algorithm for the grading of activity in
chronic hepatitis C. The METAVIR Cooperative Study Group.
Hepatology 1996; 24: 289-293.
[45] European Association for Study of Liver; Asociacion
Latinoamericana para el Estudio del Higado. EASL-ALEH Clinical
Practice Guidelines: Non-invasive tests for evaluation of liver
disease severity and prognosis. J Hepatol 2015; 63: 237-64.
[46] Stasi C, Milani S. Non-invasive assessment of liver fibrosis:
Between prediction/prevention of outcomes and cost-effectiveness.
World J Gastroenterol 2016; 22: 1711-20. doi: 10.3748/ wjg.v
22.i4.1711.
[47] Castera L, Pinzani M. Biopsy and non-invasive methods for the
diagnosis of liver fibrosis: does it take two to tango? Gut 2010; 59:
861-66.
[48] Schuppan D, Afdhal NH. Liver cirrhosis. Lancet 2008; 371: 838-
51.
[49] Abrams GA, Concato J, Fallon MB. Muscle cramps in patients
with cirrhosis. Am J Gastroenterol 1996; 91: 1363-6.
[50] Mehta SS, Fallon MB. Muscle cramps in liver disease. Clin Gas-
troenterol Hepatol 2013; 11: 1385-391.
[51] Runyon BA and the AASLD Practice Guidelines Committee. Man-
agement of adult patients with ascites due to cirrhosis: an update.
Hepatology 2009; 49: 2087-107.
[52] Gines P, Quintero E, Arroyo V, et al. Compensated cirrhosis: natu-
ral history and prognostic factors. Hepatology 1987; 7: 122-28.
Recent Advancements in Diagnosis and Therapy of Liver Cirrhosis
[53] Bosch J. Prevention of decompensation. In: AASLD (Ed) “Cirrho-
sis: current challenges and future directions”. Postgraduate Course
of the American Association for the Study of Liver Disease; 2011
Nov 4-5; Moscone West San Francisco, California, 2011: 60-5.
[54] Moreau R, Jalan R, Gines P, et al. Acute-on-chronic liver failure is
a distinct syndrome that develops in patients with acute decompen-
sation of cirrhosis. Gastroenterology 2013; 144: 1426-37.
[55] Manousou P, Dhillon AP, Isgro G, et al. Digital image analysis of
liver collagen predicts clinical outcome of recurrent hepatitis C vi-
rus 1 year after liver transplantation. Liver Transpl 2011; 17: 178-
88.
[56] Stasi C, Arena U, Vizzutti F, et al. Transient elastography for the
assessment of liver fibrosis in patients with chronic viral hepatitis:
the missing tool? Dig Liver Dis 2009; 41: 863-6.
[57] Parkes J, Roderick P, Harris S, et al. Enhanced liver fibrosis test
can predict clinical outcomes in patients with chronic liver disease.
Gut 2010; 59: 1245-51.
[58] Vergniol J, Foucher J, Terrebonne E, et al. Noninvasive tests for
fibrosis and liver stiffness predict 5-year outcomes of patients with
chronic hepatitis C. Gastroenterology 2011; 140: 1970-9.
[59] Pugh RNH, Murray-Lyon LM, Dawson JL, Pietroni MC Williams
R. Transection of the esophagus for bleeding oesophageal varices.
Br J Surg 1973; 60: 646-9.
[60] Sheth M, Riggs M, Patel T. Utility of the Mayo end-stage liver
disease (MELD) score in assessing prognosis of patients with alco-
holic hepatitis. BMC Gastroenterol 2002; 2: 2.
[61] Grace JA, Angus PW. Hepatopulmonary syndrome: update on
recent advances in pathophysiology, investigation, and treatment. J
Gastroenterol Hepatol 2013; 28: 213-9.
[62] Roisin RR, Krowka MJ. Hepatopulmonary Syndrome — A Liver-
Induced Lung Vascular Disorder. N Engl J Med 2008; 358: 2378-
87.
[63] Stasi C, Silvestri C, Voller F, Cipriani F. The epidemiological
changes of HCV and HBV infections in the era of new antiviral
therapies and the anti-HBV vaccine. J Infect Public Health 2015.
doi: 10.1016/j.jiph.2015.05.004
[64] Toccaceli F, Laghi V, Capurso L, et al. Long-term liver histology
improvement in patients with chronic hepatitis C and sustained re-
sponse to interferon. J Viral Hepat 2003; 10: 126-33.
[65] Ogawa E, Furusyo N, Toyoda K, Takeoka H, Maeda S, Hayashi J.
The longitudinal quantitative assessment by transient elastography
of chronic hepatitis C patients treated with pegylated interferon al-
pha-2b and ribavirin. Antiviral Research 2009; 83: 127-34.
[66] Heathcote EJ, Marcellin P, Buti M, et al. Three-year efficacy and
safety of tenofovir disoproxil fumarate treatment for chronic hepa-
titis B. Gastroenterology 2011; 140: 132-43.
[67] Hadziyannis SJ, Tassopoulos NC, Heathcote EJ, et al. Long term
therapy with adefovir dipivoxil for HBeAg-negative chronic hepa-
titis B for up to 5 years. Gastroenterology 2006; 131: 1743-51.
[68] Marcellin P, Gane E, Buti M, et al. Regression of cirrhosis during
treatment with tenofovir disoproxil fumarate for chronic hepatitis
B. A 5 year open label follow up study. Lancet 2013; 381: 468-75.
[69] Chang TT, Liaw YF, Wa SS, et al. Long term entecavir therapy
results in the reversal of fibrosis/cirrhosis and continued histologi-
cal improvement in patients with chronic hepatitis B. Hepatology
2010; 52: 886-93.
[70] Wiechowska A, McCullough AJ, Feldstein AE. Non invasive diag-
nosis and monitoring of non alcoholic steatohepatitis: present and
future. Hepatology 2007; 46: 582-9.
[71] Hickman IJ, Jonsson JR, Prins JB, et al. Modest weight loss and
physical activity in overweight patients with chronic liver disease
results in sustained improvements in alanine aminotransferase, fast-
ing insulin, and quality of life. Gut 2004; 53: 413-9.
[72] Kantartzis K, Thamer C, Peter A, et al. High cardiorespiratory
fitness is an independent predictor of the reduction in liver fat dur-
ing a life-style intervention in non alcoholic fatty liver disease. Gut
2009; 58: 1281-8.
[73] Tsochatzis EA, Papatheodoridis GV, Manesis EK, Kafiri G, Tini-
akos DG, Archimandritis AJ. Metabolic syndrome is associated
with severe fibrosis in chronic viral hepatitis and non-alcoholic
steatohepatitis. Aliment Pharmacol Ther 2008; 27: 80-9.
[74] Schafer S, Kantartzis K, Machann J, et al. Lifestyle intervention in
individual with normal versus impaired glucose tolerance. Eur J
Clin Invest 2007; 37: 535-43.
[75] Harrison SA, Fecht WJ, Brunt EM, Neuschwander-Tetri BA.
Orlistat for overweight subjects with nonalcoholic steatohepatitis
Current Drug Targets, 2016, Vol. 17, No. 12 13
(NASH): a randomized prospective trial. Hepatology 2009; 49: 80-
6.
[76] Naveau S, Giraud V, Borotto E, Aubert A, Capron F, Chaput JC.
Excess weight risk factor for alcoholic liver disease. Hepatology
1997; 25: 108-11.
[77] Berzigotti A, Garcia-Tsao G, Bosch J, et al. Obesity is an inde-
pendent risk factor for clinical decompensation in patients with cir-
rhosis. Hepatology 2011; 54: 555-61.
[78] Friedman SL. Mechanisms of hepatic fibrogenesis. Gastroenterol-
ogy 2008; 134: 1655-69.
[79] Friedman SL. Hepatic stellate cells: protean, multifunctional, and
enigmatic cells of the liver. Physiol Rev 2008; 88: 125-72.
[80] Falize L, Guillygomarc'h A, Perrin M, et al. Reversibility of he-
patic fibrosis in treated genetic hemochromatosis: a study of 36
cases. Hepatology 2006; 44: 472-7.
[81] Burroughs AK, Thalheimer U. Hepatic venous pressure gradient in
2010: optimal measurement is key. Hepatology 2010; 51: 1894-6.
[82] Vizzutti F, Arena U, Romanelli RG, et al. Liver stiffness measure-
ment predicts severe portal hypertension in patients with
HCV-related cirrhosis. Hepatology 2007; 45: 1290-7.
[83] Merli M, Nicolini G, Angeloni S, et al. Incidence and natural his-
tory of small esophageal varices in cirrhotic patients. J Hepatol
2003; 38: 266-72.
[84] Garcia-Tsao B, Bosch J. Management of varices and variceal hem-
orrhage in cirrhosis. N Engl J Med 2010; 362: 823-32.
[85] Schepke M, Kleber G, Numberg D, et al. Ligation versus propra-
nolol for the primary prophylaxis of variceal bleeding in cirrhosis.
Hepatology 2004; 40: 65-72.
[86] De Franchis R, Baveno V Faculty. Revising consensus in portal
hypertension: report of the Baveno V consensus workshop on
methodology of diagnosis and therapy in portal hypertension. J He-
patol 2010; 53: 762-8.
[87] D’Amico G, Crisciuoli V, Fili D, Mocciaro F, Pagliaro L. Meta-
analysis of trials for variceal bleeding. Hepatology 2002; 36: 1023-
4.
[88] Bambha K, Kim WR, Pedersen R, Bida JP, Kremers WK, Kamath
PS. Predictors of early re-bleeding and mortality after acute
variceal haemorrhage in patients with cirrhosis. Gut 2008; 57: 814-
20.
[89] Krige JE, Kotze UK, Distiller G, Shaw JM, Bornman PC. Predic-
tive factors for rebleeding and death in alcoholic cirrhotic patients
with acute variceal bleeding. A multivariate analysis. World J Surg
2009; 33: 2127-35.
[90] Bosch J, Garcia-Pagan JC. Prevention of variceal rebleeding. Lan-
cet 2003; 361: 952-4.
[91] Garcia-Pagan JC, Caca K, Bureau C, et al. Early use of TIPS in
patients with cirrhosis and variceal bleeding. N Engl J Med 2010;
362: 2370-9.
[92] Augustin S, Altamirano J, Gonzales A, et al. Effectiveness of com-
bined pharmacologic and ligation therapy in high-risk patients with
acute esophageal variceal bleeding. Am J Gastroenterol 2011; 106:
1787-95.
[93] Arvaniti V, D’Amico G, Fede G, et al. Infections in patients with
cirrhosis increase mortality four-fold and should be used in deter-
mining prognosis. Gastroenterology 2010; 139: 1246-56.
[94] Funakoshi N, Segalas-Largey F, Duny Y, et al. Benefit of combina-
tion beta-blocker and endoscopic treatment to prevent variceal
rebleeding: a meta-analysis. World J Gastroenterol 2010; 16: 5982-
92.
[95] Garcia-Tsao G, Sanyal AJ, Grace ND, Carey W. Practice Guide-
lines Committee of the American Association for the Study of
Liver Diseases; Practice Parameters Committee of the American
College of Gastroenterology. Prevention and management of gas-
troesophageal varices and variceal hemorrhage in cirrhosis. Hepa-
tology 2007; 46: 922-38.
[96] Pomier-Layrangues G. TIPS and hepatic encephalopathy. Semin
Liver Dis 1996; 16: 315-20.
[97] D’Amico G. The clinical course of cirrhosis. Population based
studies and the need of personalized medicine. J Hepatol 2014; 60:
241-2.
[98] Fede G, D’Amico G, Arvaniti V, et al. Renal failure and cir-
rhosis: a systematic review of mortality and prognosis. J He-
patol 2012; 56: 810-8.
[99] Ring-Larsen H, Henriksen JH, Wilken C, Clausen J, Pals
H, Christensen NJ. Diuretic treatment in decompensated cirrhosis
 14 Current Drug Targets, 2016, Vol. 17, No. 12
and congestive heart failure: effect of posture. Br Med J (Clin Res
Ed) 1986; 292: 1351-3.
[100] Wong F, Sniderman K, Blendis LM. The renal sympathetic and
renin-angiotensin response to lower body negative pressure in well-
compensated cirrhosis. Gastroenterology 1998; 115: 397-05.
[101] Gentilini P, Romanelli RG, Laffi G, et al. Cardiovascular and renal
function in normotensive and hypertensive patients with compen-
sated cirrhosis: effect of posture. J Hepatol 1999; 30: 632-8.
[102] Bernardi M, Laffi G, Salvagnini M, et al. Efficacy and safety of a
stepped medical care treatment of ascites in liver cirrhosis: a ran-
domized controlled clinical trial comparing two diets with different
sodium content. Liver 1993; 13: 156-62.
[103] Runyon BA. Management of adult patients with ascites due to
cirrhosis: update 2012. Available from: URL: http:
//www.aasld.org/practiceguidelines/Documents/ascitesupdate2013.
pdf.
[104] Bernardi M. Optimum use of diuretics in managing ascites in pa-
tients with cirrhosis. Gut 2010; 59: 10-1.
[105] Gentilini P, Laffi G. Renal functional impairment and sodium
retention in liver cirrhosis. Baillieres Clin Gastroenterol 1992; 6:
581-607.
[106] Santos J, Planas R, Pardo A, et al. Spironolactone alone or in com-
bination with furosemide in the treatment of moderate ascites in
nonazotemic cirrhosis. A randomized comparative study of efficacy
and safety. J Hepatol 2003; 39: 187-92.
[107] EASL. EASL clinical practice guidelines on the management of
ascites, spontaneous bacterial peritonitis, and hepatorenal syn-
drome. J Hepatol 2010; 53: 397-17.
[108] Arroyo V, Ginès P, Gerbes AL, et al. Definition and diagnostic
criteria of refractory ascites and hepatorenal syndrome in cirrhosis.
International Ascites Club. Hepatology 1996; 23: 164-76.
[109] Runyon BA. Introduction to the revised American Association for
the Study of Liver Diseases Practice guideline management of
adult patients with ascites due to cirrhosis 2012. Hepatology 2013;
57: 1651-3.
[110] O'Brien AJ, Fullerton JN, Massey KA, et al. Immunosuppression in
acutely decompensated cirrhosis is mediated by prostaglandin E2.
Nature Medicine 2014; 20: 518-23.
[111] Bernardi M, Caraceni P, Navickis RJ, Wilkes MM. Albumin
infusion in patients undergoing large-volume paracentesis: a meta-
analysis of randomized trials. Hepatology 2012; 55: 1172-81.
[112] Serste T, Melot C, Francoz C, et al. Deleterious effects of beta-
blockers on survival in patients with cirrhosis and refractory as-
cites. Hepatology 2010; 52: 1017-022.
[113] Serste T, Francoz C, Durand F, et al. Beta-blockers cause paracen-
tesis-induced circulatory dusfunction in patients with cirrhosis and
refractory ascites: a cross-over study. J Hepatol 2011; 55: 794-9.
[114] Singh V, Dhungana SP, Singh B, et al. Midodrine in patients with
cirrhosis and refractory ascites: a randomized pilot study. J Hepatol
2012; 56: 348-54.
[115] Romanelli RG, La Villa G, Barletta G, et al. Long-term albumin
infusion improve survival in patients with cirrhosis and ascites: an
unblinded randomized trial. World J Gastroenterol 2006; 12: 1403-
7.
[116] NCT01288794 “Human Albumin for the Treatment of Ascites in
Patients With Hepatic Cirrhosis (ANSWER)” find at URL: http:
//clinicaltrials.gov/show/NCT01288794.
[117] Wong F, Watson H, Gerbes A, et al. Satavaptan for the manage-
ment of ascites in cirrhosis: efficacy and safety across the spectrum
of ascites severity. Gut 2012; 61: 108-16.
[118] Bureau C, Metivier S, D’Amico M, et al. Serum bilirubin and
platelet count: a simple predictive model for survival in patients
with refractory ascites treated by TIPS. J Hepatol 2011; 54: 901-7.
[119] Claria J, Kent JD, Lopez-Parra M, et al. Effects of celecoxib and
naproxen on renal function in non azotemic patients with cirrhosis
and ascites. Hepatology 2005; 41: 579-87.
[120] Laffi G, Daskalopoulos G, Kronborg I, Hsueh W, Gentilini P,
Zipser RD. Effects of sulindac and ibuprofen in patients with cir-
rhosis and ascites. An explanation for the renal-sparing effect
of sulindac. Gastroenterology 1986; 90: 182-7.
View publication stats
Romanelli and Stasi
[121] Pariente EA, Bataille C, Bercoff E, Lebrec D. Acute effects of
captopril on systemic and renal hemodynamics and on renal func-
tion in cirrhotic patients with ascites. Gastroenterology 1985; 88:
1255-9.
[122] Gentilini P, Romanelli RG, La Villa G, et al. Effects of low dose
captopril on renal hemodynamics and function in patients with cir-
rhosis of the liver. Gastroenterology 1993; 104: 588-94.
[123] Salerno F, Gerbes A, Ginès P, Wong F, Arroyo V. Diagnosis, pre-
vention and treatment of hepatorenal syndrome in cirrhosis. Post-
grad Med J 2008; 84: 662-70.
[124] Salerno F, Cazzaniga M, Merli M, et al. Diagnosis, treatment and
survival of patients with hepatorenal syndrome: a survey on daily
medical practice. J Hepatol 2011; 55: 1241-8.
[125] Cavallin M, Kamath PS, Merli M, et al. Terlipressin versus mi-
dodrine and octreotide in the treatment of hepatorenal syndrome: a
randomized, controlled trial. Hepatology 2015; 62: 567-74.
[126] Wong W, Liu P, Blendis LM, Wong F. Long-term renal sodium
handling in patients with cirrhosis treated with transjugular intrahe-
patic portosystemic shunts for refractory ascites. Am J Med 1999;
106: 315-22.
[127] Rabie RN, Cazzaniga M, Salerno F, Wong F. The use of E/A ratio
as a predictor of outcome in cirrhotic patients treated with
transjugular intrahepatic portosystemic shunt. Am J Gastroenterol
2009; 104: 2458-66.
[128] Vizzutti F, Rega L, Arena U, et al. Paradoxical embolization in
TIPS: take a closer look to the heart. Ann Hepatol 2015; 14: 132-6.
[129] Fazekas JE, Ticktin HE, Shea JC. Effects of L-arginine on hepatic
encephalopathy. Am J Med Sci 1957; 234: 462-7.
[130] Romero-Gomez M, Boza F, Garcia-Valdecasas MS, García
E, Aguilar-Reina J. Subclinical hepatic encephalopathy predicts the
development of overt hepatic encephalopathy. Am J Gastroenterol
2001; 96: 2718-23.
[131] Kaplan PW, Rossetti AO. EEG patterns and imaging correlations in
encephalopathy: encephalopathy part II. J Clin Neurophysiol 2011;
28: 233-51.
[132] Jepsen P, Ott P, Andersen PK, Sorensen HT, Vilstrup H. Clinical
course of alcoholic liver cirrhosis: a Danish population based co-
hort study. Hepatology 2010; 51: 1675-82.
[133] D’Amico G, Morabito A, Pagliaro L, Marubini E. Survival and
prognostic indicators in compensated and decompensated cirrhosis.
Dig Dis Sci 1986; 31: 468-75.
[134] Strauss E, Tramote R, Silva EP, et al. Double-blind randomized
clinical trial comparing neomycin and placebo in the treatment of
exogenous hepatic encephalopathy. Hepatogastroenterology 1992;
39: 542-45.
[135] Sharma BC, Sharma P, Agrawal A, Sarin SK. Secondary prophy-
laxis of hepatic encephalopathy: an open-label randomized con-
trolled trial of lactulose versus placebo. Gastroenterology 2009;
137: 885-91.
[136] Bajaj JS, Sanyal AJ, Bell D, Gilles H, Heuman DM. Predictors of
the recurrence of hepatic encephalopathy in lactulose-treated pa-
tients. Aliment Pharmacol Ther 2010; 31: 1012-7.
[137] Patidar KR, Bajaj JS. Antibiotics for the treatment of hepatic en-
cephalopathy. Metab Brain Dis 2013; 28: 307-12.
[138] Bass NM, Mullen KD, Sanyal A, et al. Rifaximin treatment in
hepatic encephalopathy. N Engl J Med 2010; 362: 1071-81.
[139] Simon-Talero M, Garcia-Martinez R, Torrens M, et al. Effects of
intravenous albumin in patients with cirrhosis and episodic hepatic
encephalopathy: a randomized double-blind study. J Hepatol 2013;
59: 1184-92.
[140] Bajaj JS, Heuman DM, Wade JB, et al. Rifaximin improves driving
simulator performance in a randomized trial of patients with mini-
mal hepatic encephalopathy. Gastroenterology 2011; 140: 478-87.
[141] Kircheis G, Nilius R, Held C, et al. Therapeutic efficacy of L-
ornithine L-aspartate infusions in patients with cirrhosis and he-
patic encephalopathy: results of a placebo-controlled, double-blind
study. Hepatology 1997; 25: 1351-60.
[142] Jalan R, Wright G, Davies NA, Hodges SJ. L-ornithine phenylace-
tate: a novel treatment for hyperammonemia and hepatic encepha-
lopathy. Medical hypotheses 2007; 69: 1064-9.