Recent Advancements in Diagnosis and Therapy of

Send Orders for Reprints to [email protected] Current Drug Targets, 2016, 17, 000-000

1

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 Medicine, Azienda Ospedaliero Universitaria Careggi - AOUC Largo Brambilla, no. 3 I-50134 - Firenze Italy

ARTICLE HISTORY Received: May 26, 2015 Revised: October 07, 2015 Accepted: November 20, 2015 DOI: 10.2174/138945011766616061310 1413

Abstract: Cirrhosis is a diffuse pathophysiological state of the liver considered to be the final stage of various liver injuries, characterized by chronic necroinflammaPlease provide tory and fibrogenetic processes, with subsequent conversion of normal liver archicorresponding author(s) photograph tecture into structurally abnormal nodules, dense fibrotic septa, concomitant parensize 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 cirrhosis 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, presence 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 understanding mechanisms of fibrogenesis, the driving forces of cirrhosis’s pathogenesis, and the scrupulous approach to more effective therapeutic procedures. Prevention of fibrosis with further deterioration of liver function through specific treatments is always required, through the removal of the underlying 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 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 proliferation of connective tissue in the parenchymal liver compartment. This is caused by the necro-inflammatory and fibrogenetic processes typical of the long course of all chronic liver disease. This clinical syndrome derives from exogenous/toxic causes, infections, toxic/allergic processes, immunopathological/autoimmune causes, vascular processes or inborn errors of metabolism. The pathological process of liver cirrhosis is characterized by diffuse nodular regeneration that replaces normal liver architecture, together with the production of dense fibrotic septa, concomitant parenchymal exhaustment, and the final collapse of the liver tissue. Eventually, the organ’s original structure is completely lost and a concomitant profound distortion of the hepatic vascular *Addresss correspondence to this author at the Department of Experimental and Clinical Medicine (DMSC) and Liver Unit; University of FlorenceSchool 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: [email protected] 1389-4501/16 $58.00+.00

architecture frequently occurs. In current practice, common 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, hepatic 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 carcinoma, some of which capable to decrease survival rate [1]. Necro-inflammatory-regenerative processes through intermediately 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 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 © 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 information 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 cirrhosis are chronic viral hepatitis, due to HBV or HCV, alcohol 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 nodules 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 capillarization 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 pressure 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, hepatocellular carcinoma) [15]. Contributing factors are represented by an imbalance among vasodilating (especially nitric oxide) and vasoconstricting (especially endothelins) molecules, which eventually leads to increased intrahepatic resistance 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 increase 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 delivery of dietary sodium with a positive sodium balance (sodium 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 presence of peripheral arterial vasodilation, especially in the splanchnic compartment, characterized by increased venous pre-load and cardiac output, together with decreased peripheral 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 vasoconstricting and antidiuretic vasoactive systems, such as the renin-angiotensin-aldosterone system and the sympathetic nervous system, which, in turn, creates, together with a nonosmotic 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 sodium 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 vasoconstricting 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 vasoconstriction 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 vascular oncotic pressure due to hypoalbuminemia in the pathogenesis 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 driving force for colloidal osmotic pressure and may directly influence vascular integrity and permeability by way of interactions 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 varying widths divide the hepatic parenchyma into nodules. Several hepatic nodules have vascular structures that may or may not represent terminal 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 phenomena 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 – Septal 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 cirrhosis. 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).


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 comorbidities such as metabolic syndrome, prolonged ethanol intake, or exposure to hepatotoxic substances. Some clinical manifestations are represented by anorexia, body weight loss, weakness, fatigue, jaundice, pruritus, spider angiomata, gynecomastia, increased abdominal girth due to ascites, splenomegaly, 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 probable 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 characterized 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 shunting (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 folliclestimulating hormone (FSH) and luteinizing hormone (LH) are increased [22]. Females often develop anovulation, amerorrhea 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 associated 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 palpation, some risk constellations, such as a metabolic syndrome, heavy alcohol consumption, exposure to hepatotoxic substances, and the use of hepatotoxic medications. Cirrhotic patients with ascites present an elevated risk for the development 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 ultrasound reveals an inhomogeneity of the hepatic tissue, an irregular liver surface, caudate and left lobes enlargement. Transient elastography and the acoustic radiation force impulse (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 consequent splenomegaly. Physicians should also monitor their patients for early screening of liver cirrhosis by means of transient elastography (Fibroscan), if available. Liver stiffness 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 elastography for the assessment of short- and long-term longitudinal 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 longitudinal variation in liver fibrosis. Notwithstanding, it is mandatory 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 diagnosis. 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 determination, transjugular intrahepatic portosystemic shunt (TIPS) through the suprahepatic veins and the portal collaterals) [30]. Cirrhotic cardiomyopathy, frequently observed in advanced phase of the disease, is represented by a chronic cardiac dysfunction with impaired contractile responsiveness to stress and/or altered diastolic relaxation (diastolic dysfunction) with electrophysiological abnormalities in the absence of other known cardiac diseases, which is much more diagnosed not only through the increased plasma levels of probrain natriuretic peptide, but also by challenging patients with exercise and the consequent demonstration of QT adaptation, 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 account 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 procedure with several limitations in patients with decompensated cirrhosis, because it is often accompanied by complications,


Table 1.


5

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 recent 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 samples from liver transplant patients with chronic hepatitis Binduced decompensated cirrhosis. In this study, the CPA of liver tissue was as low as 11.24% in some patients. The patients 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 (0.48). 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 disease itself. Recently, Tsochatzis et al. [33] compared the performance of histological semi-quantitative and quantitative methods specifically developed for sub-classifying cirrhosis with CPA in patients with alcoholic liver disease, HCV, HBV nonalcoholic steatohepatitis, autoimmune hepatitis. They found that CPA accurately sub-classified cirrhosis

and it is the only independent predictor of clinical decompensation among the other histological systems described to date. Non-invasive serum markers may also be used for making 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 collagen, 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 semiquantitative 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 methods to assess a wide range of chronic liver diseases [for extensive review see 45-47]. Information given by these markers 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 developing future antifibrotic therapies. All such tests should only be used and verified on patients having a definite etiological diagnosis of liver disease.


Table 2.

Romanelli and Stasi

Some non invasive markers in CLD. Extensive Fibrosis or Cirrhosis

No. Items

Age

Age-platelet index [34]

2

*

*

-

-

AST-ALT [34]

2

-

-

*

APRI [35]

2

-

*

*

ELF score [36]

3 or 4

*/#

-

FIB 4 [37]

4

*

Fibronectin [38]

4

-

PLT

AST

ALT

Other Cut-off

Sensitivity (%)

Specificity

PPV (%)

NPV (%)

-

>6

35.9

85.6

10.8

96.5

*

-

>1

38.5

71.5

6.1

96

-

-

2

65

95

-

-

hyaluronic acid N-propept. type II collagen – TIMP1 levels

>9.30

79.1

90.8

75.6

92.3

*

*

*

-

>3.25

59.2

82.3

64

79.2

*

*

-

serum albumin levels – Fibronectin levels

>415 mg/dl

60

58

59

44

0.8

38

97

92

62

FibroTest [39]

7

*

-

-

-

α2 macroglobulin – haptoglobin apolipoprotein A-1 – γGT - total bilirubin (gammaglobulin in original version) levels – sex

Forns [40]

4

*

*

-

-

γGT - cholesterol levels

>6.90

41.9

92.9

85.7

61.2

GUCI [41]

3

-

*

*

-

prothrombin index

1

80

78

31

97

>0.87

33

92

81.1

56.7

Hepascore [40]

6

*

-

-

-

α2 macroglobulin – γGT - hyaluronic acid - bilirubin levels - sex

King’s score [34]

4

*

*

*

-

INR

>16.7

69.2

73.8

11.4

98

Lok [34]

4

-

*

*

*

INR

>0.5

94.9

18.1

7.8

96.5

MP3 score [40]

2

-

-

-

-

MMP-1 - PIIIP levels

>0.50

18.7

98.9

94.4

54.0

Pohl index [42]

3

-

*

*

*

-

1

50.0

94.3

63.6

90.4

*

INR - right hepatic lobe atrophy splenomegaly caudate lobe hyperthrophy

>6

72

75

81

63.7

Sabadell NIHCED [43]

8

*

*

*

The consequences of decompensated cirrhosis are thrombocytopenia 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 cholestatic indexes, such as gamma-glutamyltranpeptidase (γ-

GT) and alkaline phosphatase, together with total bilirubin. Cytolytic markers (alanine aminotransferase –AST- and aspartate aminotransferase –ALT-) are often within the normal range or slightly higher [48]. Some patients with liver cirrhosis may have severe muscle cramps [49, 50] and possibly this may be due to a reduction in circulating plasma volume.



In the absence of a clear diagnosis of liver cirrhosis, contemporary determinations of serum and ascitic albumin concentrations are useful for the determination of serum albumin ascites gradient. When this gradient is > 1.1 g/dL, a conceivable diagnosis of portal hypertension is obtainable [51]. Table 3.

Score of liver fibrosis according to METAVIR score [44].

No fibrosis

0

Stellate enlargement of portal tract but without septa formation

1

Enlargement of portal tract with rare septa formation

2

Numerous septa formation

3

Cirrhosis

4

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 hypertension, markedly increase mortality rate [52]. Subsequent studies 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 followup [1, 52]. When there are no varices, the “compensated” stage of the disease, is characterized by a less than 10% mortality rate [1]. According to D’Amico et al. [1], it is possible to identify different phases of liver cirrhosis, each characterized 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 characterized by the presence of ascites, with a 20% mortality rate/year. The fourth is characterized by bleeding from gastrointestinal varices and has 57% mortality rate/year. The last phase is characterized by further complications of liver cirrhosis (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 previous 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 proportionate area (CPA) determinations, together with portal pressure measurements (HVPG determination), may add some useful information and offer some valid help in making disease 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 natural course of the disease [46, 57, 58]. When the decompen-

7

sated disease is associated with major complications (ascites, gastrointestinal bleeding, hepatic failure, jaundice and hepatocellular 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 accumulation, serum albumin concentration, prothrombin (INR) time, serum bilirubin levels, serum sodium concentration, and serum creatinine levels [59, 60]. The hepatopulmonary syndrome (HPS), characterized by defects in oxygenation due to pulmonary abnormalities, is associated with advanced liver disease and occurs in 10-32% of cirrhotic patients. Dyspnea and hypoxemia can be severe and often worsen in the upright position. Gross dilatation of the precapillary and capillary vessels occurs with ventilation–perfusion mismatch. The syndrome usually improves after liver transplantation [61, 62]. The disease progression is shown in (Fig. 3). PREVENTION AND TREATMENT OF COMPLICATIONS 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 ultrasonography 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 further 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 response 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 viremic patients with CLD (either HBV or HCV positive subjects), 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 compensated one [66]. Treatment of HBV or HCV infections with


Romanelli and Stasi

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 improvement over a period of 240 weeks [67]. The nucleoside/nucleotide analogs cause viral suppression of over 99%, the regression of fibrosis. The disadvantages include the unlimited duration of treatment, the low rate of loss of HBsAg and the seroconversion to anti-HBs. Treatment with tenofovir for 5 years resulted in liver fibrosis regression in cirrhotic 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 influenced 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 syndrome 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 lifestyle 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 modification, diet and physical activity for 48 weeks, 200 min-

utes/week) versus structured basic education alone. Patients undergoing lifestyle interventions registered almost a 10% weigh loss reduction together with improvements in steatosis, 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 slowing 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 decompression [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 venous pressure gradient (HVPG) is the current standard technique 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


HVPG is a relatively new approach and is an accurate prognostic 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 progression 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 clinically 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 gastrointestinal 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 bleeding, liver failure, hepatic encephalopathy, refractory ascites and increased susceptibility to infections) and a poor prognosis within this first year after the initial episode of bleeding, the prevention of variceal bleeding is mandatory. Therapeutic 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 diameter 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 efficacy 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 presence of decompensated cirrhosis (ascites) and a plasma bilirubin 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 antibiotics 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 because they have recurrent variceal hemorrhage despite combined 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


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 prevention 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 studies. 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 favours 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%, especially 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 sodium 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 (canrenoate potassium or canrenone, its active metabolite) and high-ceiling diuretics (furosemide, torasemide) [103]. Dietary fluid restriction is limited to the patients who have low plasma sodium concentrations (below 120 mEq/L), because


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 recurrent 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 ascites, 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 treatment for first-case ascites, and combined therapy for recurrent 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 patients with ascites and peripheral edema, and 0.5 Kg per day in patients having only ascites [108]. Hydro-electrolyte imbalances 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 diuretics. 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 becomes progressively untreatable or unsusceptible to treatment without the onset of serious collateral side effects [109]. Large volume paracentesis is reserved to grade 3 ascites, together with compensating i.v. human albumin infusion (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 production in vitro. As a result, human albumin solution infusions can be beneficial, as we observed in our clinical experience, 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 recently 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 paracentesis-induced circulatory dysfunction (PICD). In this study population, some authors demonstrated that nonselective beta-blockers, such as propranolol, give poor results, especially in the case of paracentesis-induced circulatory 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 arterial 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 diureticsensitive one [114]. As compared to diuretic treatment alone,

Romanelli and Stasi

hospital stay is significantly reduced, as are all severe sideeffects, 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 discovered drug family in the treatment of ascites consists in vaptans, 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 benefits 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 orthotopic 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 prostaglandin synthesis. Furthermore, hyponatremia, diuretic resistance 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 ascites due to the onset of arterial hypotension and the development 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 functional 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 indexes 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 spontaneous bacterial peritonitis. It is conceivable that efficacious prevention of spontaneous bacterial peritonitis through correct diagnosis and appropriate treatment can prevent the onset 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, midodrine, 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


favour terlipressin plus albumin infusion treatment compared to other therapeutic procedures [125]. Nowadays, TIPS insertion 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 lowsodium 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 responding with complete disappearance of ascites. These results 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 debilitating complications of liver disease. Advanced liver disease and portosystemic shunting have well-known consequences on the body and brain functioning. Alterations in brain functioning, which can produce behavioral, cognitive, and motor effects, were termed portosystemic encephalopathy, and later included in the term HE [129]. The prevalence of this disorder at the time of diagnosis of cirrhosis is usually 10-14% [130]. This complication is usually associated with poor survival rate and a high risk of recurrence [131] since the mortality rate goes up to 64% [132]. Precipitating events of HE commonly consist in constipation, dehydration, infection/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 administered at a starting dose of 25 mL of syrup every 12 h, and then increased until at least two soft or loose bowel movements 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 improvement and ammonia lowering [138]. Rifaximin and lactulose together are effective in the treatment of HE and reduce the recurrence risk by about 25%. Furthermore, rifaximin 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-


11

related life quality and enhance driving skills, especially when patients are affected by both overt HE and the socalled 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 venous 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 production, 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 carcinoma. 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 further studies. The hepatorenal syndrome seems to improve when treated by terlipressin plus human albumin administration. 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 conflict 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] [2] [3] [4] [5]

D’Amico G, Garcio-Tsao G, Pagliaro L. Natural history and prognostic indicators of survival in cirrhosis: a systematic review of 118 studies. J Hepatol 2006; 44: 217-31. Britton RS, Brown KE. Genetic hemochromatosis and Wilson’s disease: role for oxidant stress? Hepatology 1995; 21: 1195-97. Camaschella C. Treating iron overload. N Engl J Med 2013; 368: 2325-27. Deutsch M, Emmanuel T, Koskinas J. Autoimmune hepatitis or Wilson’s disease: a clinical dilemma. Hepat Mon 2013; 13: e7872. Wu SJ, Yang YH, Tsuneyama K, et al. Innate immune and primary biliary cirrhosis: activated invariant natural killer T cells exhacerbate murine autoimmune cholangitis and fibrosis. Hepatology 2011; 53: 915-25.

12 Current Drug Targets, 2016, Vol. 17, No. 12 [6] [7]

[8]

[9] [10] [11]

[12] [13] [14]

[15]

[16] [17] [18] [19]

[20] [21] [22] [23] [24] [25] [26]

[27]

[28]

Poupon R, Chazouilleres O, Corpechot C, Chretien Y. Development of autoimmune hepatitis in patients with typical autoimmune hepatitis. Hepatology 2006; 44: 85-90. 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. 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. 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. 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. 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. 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. Perz JF, Armstrong GL, Farrington LA, Hutin YJ, Bell BP. The contributions of hepatitis C virus infections to cirrhosis and primary liver cancer worldwide. J Hepatol 2006; 45: 529-38. Lozano R, Naghavi M, Foreman K, et al. Global and regional mortality 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. 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: Churchill Livingstone; 2012: 1-78. Minano C, Garcia-Tsao G. Clinical pharmacology of portal hypertension. Gastroenterol Clin North Am 2010; 39: 681-95. Wiest R, Groszmann RJ. The paradox of nitric oxide in cirrhosis and portal hypertension: too much, not enough. Hepatology 2002; 35: 478-91. Borzio M, Salerno F, Piantoni L, et al. Bacterial infection in patients with advanced cirrhosis: a multicentre prospective study. Dig Liver Dis 2011; 33: 41-8. Jalan R, Schnurr K, Mookerjee RP, et al. Alterations in the functional capacity of albumin in patients with decompensated cirrhosis is associated with increased mortality. Hepatology 2009; 50: 55564. Martinez GP, Barbera JA, Visa J, et al. Hepatopulmonary syndrome in candidates for liver transplantation. J Hepatol 2001; 34: 651-7. Tangerman A, Meuwese-Arends MT, Jansen JB. Causes and composition of foetor hepaticus. Lancet 1994; 343: 1569. Van Thiel DH, Gavaler JS, Spero JA, et al. Patterns of hypothalamic-pituitary-gonadal dysfunction in men with liver disease due to different etiologies. Hepatology 1981; 1: 39-46. Burra P, Germani G, Masier A, et al. Sexual dysfunction in chronic liver disease: is liver transplantation an effective cure? Transplantation 2010; 89: 1425-9. Cundy TF, Butler J, Pope RM, Saggar-Malik AK, Wheeler MJ, Williams R. Amenorrhoea in women with non-alcoholic liver disease. Gut 1991; 32: 202-06. Van Thiel DH, Gavaler JS, Schade RR. Liver disease and the hypothalamic pituitary gonadal axis. Semin Liver Dis 1985; 5: 35-45. 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. 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. 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] [30] [31] [32]

[33] [34] [35]

[36]

[37] [38] [39] [40] [41]

[42]

[43]

[44] [45]

[46]

[47] [48] [49] [50] [51] [52]

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 Cholongitas E, Quaglia A, Samonakis D, et al. Transjugular liver biopsy: how good is it for accurate histological interpretation? Gut 2006; 55: 1789-94. 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. 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. 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. Shehab H, Elattar I, Elbaz T, Mohey M, Esmat G. CUFA algorithm: assessment of liver fibrosis using routine laboratory data. J Viral Hepat 2014; 21: 956-64. 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 hepatitis C. Hepatology 2003; 38: 518-26. 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: 50007. 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. 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. 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. 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. Islam S, Antonsson L, Westin J, Lagging M. Cirrhosis in hepatitis C virus-infected patients can be excluded using an index of standard biochemical serum markers. Scand J Gastroenterol 2005; 40: 867-72. 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. 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. 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. 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. 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. 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. Schuppan D, Afdhal NH. Liver cirrhosis. Lancet 2008; 371: 83851. Abrams GA, Concato J, Fallon MB. Muscle cramps in patients with cirrhosis. Am J Gastroenterol 1996; 91: 1363-6. Mehta SS, Fallon MB. Muscle cramps in liver disease. Clin Gastroenterol Hepatol 2013; 11: 1385-391. Runyon BA and the AASLD Practice Guidelines Committee. Management of adult patients with ascites due to cirrhosis: an update. Hepatology 2009; 49: 2087-107. Gines P, Quintero E, Arroyo V, et al. Compensated cirrhosis: natural history and prognostic factors. Hepatology 1987; 7: 122-28.

Recent Advancements in Diagnosis and Therapy of Liver Cirrhosis [53]

[54] [55]

[56] [57] [58] [59] [60] [61] [62] [63]

[64] [65]

[66] [67] [68] [69]

[70] [71]

[72]

[73]

[74] [75]

Bosch J. Prevention of decompensation. In: AASLD (Ed) “Cirrhosis: 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. Moreau R, Jalan R, Gines P, et al. Acute-on-chronic liver failure is a distinct syndrome that develops in patients with acute decompensation of cirrhosis. Gastroenterology 2013; 144: 1426-37. Manousou P, Dhillon AP, Isgro G, et al. Digital image analysis of liver collagen predicts clinical outcome of recurrent hepatitis C virus 1 year after liver transplantation. Liver Transpl 2011; 17: 17888. 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. 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. 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. 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. Sheth M, Riggs M, Patel T. Utility of the Mayo end-stage liver disease (MELD) score in assessing prognosis of patients with alcoholic hepatitis. BMC Gastroenterol 2002; 2: 2. Grace JA, Angus PW. Hepatopulmonary syndrome: update on recent advances in pathophysiology, investigation, and treatment. J Gastroenterol Hepatol 2013; 28: 213-9. Roisin RR, Krowka MJ. Hepatopulmonary Syndrome — A LiverInduced Lung Vascular Disorder. N Engl J Med 2008; 358: 237887. 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 Toccaceli F, Laghi V, Capurso L, et al. Long-term liver histology improvement in patients with chronic hepatitis C and sustained response to interferon. J Viral Hepat 2003; 10: 126-33. 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 alpha-2b and ribavirin. Antiviral Research 2009; 83: 127-34. Heathcote EJ, Marcellin P, Buti M, et al. Three-year efficacy and safety of tenofovir disoproxil fumarate treatment for chronic hepatitis B. Gastroenterology 2011; 140: 132-43. Hadziyannis SJ, Tassopoulos NC, Heathcote EJ, et al. Long term therapy with adefovir dipivoxil for HBeAg-negative chronic hepatitis B for up to 5 years. Gastroenterology 2006; 131: 1743-51. 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. Chang TT, Liaw YF, Wa SS, et al. Long term entecavir therapy results in the reversal of fibrosis/cirrhosis and continued histological improvement in patients with chronic hepatitis B. Hepatology 2010; 52: 886-93. Wiechowska A, McCullough AJ, Feldstein AE. Non invasive diagnosis and monitoring of non alcoholic steatohepatitis: present and future. Hepatology 2007; 46: 582-9. 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, fasting insulin, and quality of life. Gut 2004; 53: 413-9. Kantartzis K, Thamer C, Peter A, et al. High cardiorespiratory fitness is an independent predictor of the reduction in liver fat during a life-style intervention in non alcoholic fatty liver disease. Gut 2009; 58: 1281-8. Tsochatzis EA, Papatheodoridis GV, Manesis EK, Kafiri G, Tiniakos 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. 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. Harrison SA, Fecht WJ, Brunt EM, Neuschwander-Tetri BA. Orlistat for overweight subjects with nonalcoholic steatohepatitis


[76] [77] [78] [79] [80] [81] [82] [83] [84] [85] [86]

[87] [88]

[89]

[90] [91] [92]

[93] [94]

[95]

[96] [97] [98] [99]

13

(NASH): a randomized prospective trial. Hepatology 2009; 49: 806. 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. Berzigotti A, Garcia-Tsao G, Bosch J, et al. Obesity is an independent risk factor for clinical decompensation in patients with cirrhosis. Hepatology 2011; 54: 555-61. Friedman SL. Mechanisms of hepatic fibrogenesis. Gastroenterology 2008; 134: 1655-69. Friedman SL. Hepatic stellate cells: protean, multifunctional, and enigmatic cells of the liver. Physiol Rev 2008; 88: 125-72. Falize L, Guillygomarc'h A, Perrin M, et al. Reversibility of hepatic fibrosis in treated genetic hemochromatosis: a study of 36 cases. Hepatology 2006; 44: 472-7. Burroughs AK, Thalheimer U. Hepatic venous pressure gradient in 2010: optimal measurement is key. Hepatology 2010; 51: 1894-6. Vizzutti F, Arena U, Romanelli RG, et al. Liver stiffness measurement predicts severe portal hypertension in patients with HCV-related cirrhosis. Hepatology 2007; 45: 1290-7. Merli M, Nicolini G, Angeloni S, et al. Incidence and natural history of small esophageal varices in cirrhotic patients. J Hepatol 2003; 38: 266-72. Garcia-Tsao B, Bosch J. Management of varices and variceal hemorrhage in cirrhosis. N Engl J Med 2010; 362: 823-32. Schepke M, Kleber G, Numberg D, et al. Ligation versus propranolol for the primary prophylaxis of variceal bleeding in cirrhosis. Hepatology 2004; 40: 65-72. 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 Hepatol 2010; 53: 762-8. D’Amico G, Crisciuoli V, Fili D, Mocciaro F, Pagliaro L. Metaanalysis of trials for variceal bleeding. Hepatology 2002; 36: 10234. 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: 81420. Krige JE, Kotze UK, Distiller G, Shaw JM, Bornman PC. Predictive factors for rebleeding and death in alcoholic cirrhotic patients with acute variceal bleeding. A multivariate analysis. World J Surg 2009; 33: 2127-35. Bosch J, Garcia-Pagan JC. Prevention of variceal rebleeding. Lancet 2003; 361: 952-4. 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. Augustin S, Altamirano J, Gonzales A, et al. Effectiveness of combined pharmacologic and ligation therapy in high-risk patients with acute esophageal variceal bleeding. Am J Gastroenterol 2011; 106: 1787-95. Arvaniti V, D’Amico G, Fede G, et al. Infections in patients with cirrhosis increase mortality four-fold and should be used in determining prognosis. Gastroenterology 2010; 139: 1246-56. Funakoshi N, Segalas-Largey F, Duny Y, et al. Benefit of combination beta-blocker and endoscopic treatment to prevent variceal rebleeding: a meta-analysis. World J Gastroenterol 2010; 16: 598292. Garcia-Tsao G, Sanyal AJ, Grace ND, Carey W. Practice Guidelines Committee of the American Association for the Study of Liver Diseases; Practice Parameters Committee of the American College of Gastroenterology. Prevention and management of gastroesophageal varices and variceal hemorrhage in cirrhosis. Hepatology 2007; 46: 922-38. Pomier-Layrangues G. TIPS and hepatic encephalopathy. Semin Liver Dis 1996; 16: 315-20. D’Amico G. The clinical course of cirrhosis. Population based studies and the need of personalized medicine. J Hepatol 2014; 60: 241-2. Fede G, D’Amico G, Arvaniti V, et al. Renal failure and cirrhosis: a systematic review of mortality and prognosis. J Hepatol 2012; 56: 810-8. Ring-Larsen H, Henriksen JH, Wilken C, Clausen J, Pals H, Christensen NJ. Diuretic treatment in decompensated cirrhosis


[100] [101] [102]

[103]

[104] [105] [106]

[107] [108] [109]

[110] [111] [112] [113] [114] [115]

[116] [117] [118] [119] [120]

and congestive heart failure: effect of posture. Br Med J (Clin Res Ed) 1986; 292: 1351-3. Wong F, Sniderman K, Blendis LM. The renal sympathetic and renin-angiotensin response to lower body negative pressure in wellcompensated cirrhosis. Gastroenterology 1998; 115: 397-05. Gentilini P, Romanelli RG, Laffi G, et al. Cardiovascular and renal function in normotensive and hypertensive patients with compensated cirrhosis: effect of posture. J Hepatol 1999; 30: 632-8. Bernardi M, Laffi G, Salvagnini M, et al. Efficacy and safety of a stepped medical care treatment of ascites in liver cirrhosis: a randomized controlled clinical trial comparing two diets with different sodium content. Liver 1993; 13: 156-62. Runyon BA. Management of adult patients with ascites due to cirrhosis: update 2012. Available from: URL: http: //www.aasld.org/practiceguidelines/Documents/ascitesupdate2013. pdf. Bernardi M. Optimum use of diuretics in managing ascites in patients with cirrhosis. Gut 2010; 59: 10-1. Gentilini P, Laffi G. Renal functional impairment and sodium retention in liver cirrhosis. Baillieres Clin Gastroenterol 1992; 6: 581-607. Santos J, Planas R, Pardo A, et al. Spironolactone alone or in combination 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. EASL. EASL clinical practice guidelines on the management of ascites, spontaneous bacterial peritonitis, and hepatorenal syndrome. J Hepatol 2010; 53: 397-17. 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. 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. 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. Bernardi M, Caraceni P, Navickis RJ, Wilkes MM. Albumin infusion in patients undergoing large-volume paracentesis: a metaanalysis of randomized trials. Hepatology 2012; 55: 1172-81. Serste T, Melot C, Francoz C, et al. Deleterious effects of betablockers on survival in patients with cirrhosis and refractory ascites. Hepatology 2010; 52: 1017-022. Serste T, Francoz C, Durand F, et al. Beta-blockers cause paracentesis-induced circulatory dusfunction in patients with cirrhosis and refractory ascites: a cross-over study. J Hepatol 2011; 55: 794-9. 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. 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: 14037. NCT01288794 “Human Albumin for the Treatment of Ascites in Patients With Hepatic Cirrhosis (ANSWER)” find at URL: http: //clinicaltrials.gov/show/NCT01288794. Wong F, Watson H, Gerbes A, et al. Satavaptan for the management of ascites in cirrhosis: efficacy and safety across the spectrum of ascites severity. Gut 2012; 61: 108-16. 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. 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. Laffi G, Daskalopoulos G, Kronborg I, Hsueh W, Gentilini P, Zipser RD. Effects of sulindac and ibuprofen in patients with cirrhosis and ascites. An explanation for the renal-sparing effect of sulindac. Gastroenterology 1986; 90: 182-7.

Romanelli and Stasi [121]

[122] [123] [124] [125] [126]

[127]

[128] [129] [130]

[131] [132] [133] [134]

[135]

[136] [137] [138] [139]

[140] [141]

[142]

Pariente EA, Bataille C, Bercoff E, Lebrec D. Acute effects of captopril on systemic and renal hemodynamics and on renal function in cirrhotic patients with ascites. Gastroenterology 1985; 88: 1255-9. Gentilini P, Romanelli RG, La Villa G, et al. Effects of low dose captopril on renal hemodynamics and function in patients with cirrhosis of the liver. Gastroenterology 1993; 104: 588-94. Salerno F, Gerbes A, Ginès P, Wong F, Arroyo V. Diagnosis, prevention and treatment of hepatorenal syndrome in cirrhosis. Postgrad Med J 2008; 84: 662-70. 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. Cavallin M, Kamath PS, Merli M, et al. Terlipressin versus midodrine and octreotide in the treatment of hepatorenal syndrome: a randomized, controlled trial. Hepatology 2015; 62: 567-74. Wong W, Liu P, Blendis LM, Wong F. Long-term renal sodium handling in patients with cirrhosis treated with transjugular intrahepatic portosystemic shunts for refractory ascites. Am J Med 1999; 106: 315-22. 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. 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. Fazekas JE, Ticktin HE, Shea JC. Effects of L-arginine on hepatic encephalopathy. Am J Med Sci 1957; 234: 462-7. 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. Kaplan PW, Rossetti AO. EEG patterns and imaging correlations in encephalopathy: encephalopathy part II. J Clin Neurophysiol 2011; 28: 233-51. Jepsen P, Ott P, Andersen PK, Sorensen HT, Vilstrup H. Clinical course of alcoholic liver cirrhosis: a Danish population based cohort study. Hepatology 2010; 51: 1675-82. 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. 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. Sharma BC, Sharma P, Agrawal A, Sarin SK. Secondary prophylaxis of hepatic encephalopathy: an open-label randomized controlled trial of lactulose versus placebo. Gastroenterology 2009; 137: 885-91. Bajaj JS, Sanyal AJ, Bell D, Gilles H, Heuman DM. Predictors of the recurrence of hepatic encephalopathy in lactulose-treated patients. Aliment Pharmacol Ther 2010; 31: 1012-7. Patidar KR, Bajaj JS. Antibiotics for the treatment of hepatic encephalopathy. Metab Brain Dis 2013; 28: 307-12. Bass NM, Mullen KD, Sanyal A, et al. Rifaximin treatment in hepatic encephalopathy. N Engl J Med 2010; 362: 1071-81. 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. Bajaj JS, Heuman DM, Wade JB, et al. Rifaximin improves driving simulator performance in a randomized trial of patients with minimal hepatic encephalopathy. Gastroenterology 2011; 140: 478-87. Kircheis G, Nilius R, Held C, et al. Therapeutic efficacy of Lornithine L-aspartate infusions in patients with cirrhosis and hepatic encephalopathy: results of a placebo-controlled, double-blind study. Hepatology 1997; 25: 1351-60. Jalan R, Wright G, Davies NA, Hodges SJ. L-ornithine phenylacetate: a novel treatment for hyperammonemia and hepatic encephalopathy. Medical hypotheses 2007; 69: 1064-9.

Recent Advancements in Diagnosis and Therapy of

Recent Advancements in Diagnosis and Therapy of

Suggest Documents

Recent advancements in erythrocytes, platelets

Recent Advancements in Stereoselective Olefin

Recent Advances in Cell Biology, Diagnosis and Therapy of ...

Recent advancements in the drug treatment of

Recent Advancements in Diagnostic Aids in ...

Recent Advancements in Diagnostic Aids in

Recent advancements in surface plasmon polaritons ...

Recent Advancements in Food Waste Management - ijoart

Recent advancements in oxadiazole-based anticancer agents

Recent advancements in Whole Powder Pattern

Recent Advancements in Pancreatic Cancer Immunotherapy

Recent Advancements in Ligament Replacement

Recent Advancements in Ligament Tissue Engineering

Recent Advancements in Liquid Metal Flexible

Recent advancements in fluoride: A systematic review

Recent Advancements in Autologous Fat Grafting

Current Issues, Recent Advancements, and Future ...

Recent Advancements in Diabetes Pharmacotherapy - Semantic Scholar

Recent Advancements in Event Processing - GitHub Pages

Fundamental Issues and Recent Advancements in Analysis of Aircraft ...

Recent Advancements in the Regeneration of Auditory Hair Cells and

Recent Advancements in M2M Communications in 4G Networks and ...

Fundamental Issues and Recent Advancements in Analysis of Aircraft ...

Fundamental Issues and Recent Advancements in Analysis of Aircraft