Liver Cirrhosis Pere Gines

Seminar
Liver cirrhosis
Pere Ginès, Aleksander Krag, Juan G Abraldes, Elsa Solà, Núria Fabrellas, Patrick S Kamath
Cirrhosis is widely prevalent worldwide and can be a consequence of different causes, such as obesity, non-alcoholic Lancet 2021; 398: 1359–76
fatty liver disease, high alcohol consumption, hepatitis B or C infection, autoimmune diseases, cholestatic diseases, Published Online
and iron or copper overload. Cirrhosis develops after a long period of inflammation that results in replacement of the September 17, 2021
https://doi.org/10.1016/
healthy liver parenchyma with fibrotic tissue and regenerative nodules, leading to portal hypertension. The disease S0140-6736(21)01374-X
evolves from an asymptomatic phase (compensated cirrhosis) to a symptomatic phase (decompensated cirrhosis), the
Liver Unit, Hospital Clinic of
complications of which often result in hospitalisation, impaired quality of life, and high mortality. Progressive portal Barcelona, Barcelona, Spain
hypertension, systemic inflammation, and liver failure drive disease outcomes. The management of liver cirrhosis is (Prof P Ginès MD,
centred on the treatment of the causes and complications, and liver transplantation can be required in some cases. In Prof E Solà MD); Faculty of
Medicine and Health Sciences,
this Seminar, we discuss the disease burden, pathophysiology, and recommendations for the diagnosis and
University of Barcelona,
management of cirrhosis and its complications. Future challenges include better screening for early fibrosis or Barcelona, Spain (Prof P Ginès,
cirrhosis, early identification and reversal of causative factors, and prevention of complications. Prof E Solà,
Prof N Fabrellas PhD); Institute
Introduction relevance of cirrhosis is still low and the disease is not of Biomedical Investigation
August Pi I Sunyer, Barcelona,
Liver cirrhosis is widely prevalent in both low-income and commonly diagnosed during the development phase, Spain (Prof P Ginès,
middle-income countries and in high-income countries, which leads to missed opportunities to mitigate causative Prof N Fabrellas); Hepatic and
and is associated with high morbidity and mortality.1 factors and prevent subsequent progression. Digestive Diseases Biomedical
Investigation Center, Madrid,
Cirrhosis is a consequence of chronic liver inflammation Important research efforts over the past 20 years Spain (Prof P Ginès,
that is followed by diffuse hepatic fibrosis, wherein the have improved our understanding of the pathogenesis, Prof N Fabrellas); Centre for
normal hepatic architecture is replaced by regenerative diagnosis, and treatment of the disease. In this Seminar, Liver Research, Department of
hepatic nodules, which eventually leads to liver failure.2 we summarise the current understanding of cirrhosis, and Gastroenterology and
Hepatology, Odense University
Chronic liver inflammation does not progress to cirrhosis present a brief discussion on hepatocellular carcinoma. Hospital, Odense, Denmark
in all patients, but when progression does occur, the rate (Prof A Krag MD); Institute of
at which it happens varies from weeks (in patients with Global burden of cirrhosis Clinical Research, University of
complete biliary obstruction) to decades (in patients with About 2 million deaths worldwide annually are attri Southern Denmark, Odense,
Denmark (Prof A Krag);
longer-term causes, such as viral hepatitis C). The butable to liver disease: 1 million due to cirrhosis and Liver Unit, Division of
asymptomatic (initial) phase of cirrhosis can be followed 1 million due to viral hepatitis and hepatocellular Gastroenterology, University
by a relatively short symptomatic phase of months to carcinoma. More than 60% of all liver disease-related of Alberta, Edmonton, AB,
years. The symptomatic phase, usually designated as deaths are in men.1 Cirrhosis is the 11th most common Canada (Prof J G Abraldes MD);
Institute for Immunity,
decompensated cirrhosis, is associated with various cause of death, the third leading cause of death in people Transplantation and Infection,
complications that result in frequent hospital admission, aged 45–64 years, and together with liver cancer, accounts Stanford University, Stanford,
impaired quality of life of patients and caregivers, and for 3·5% of all deaths worldwide.10 Age-standardised CA, USA (Prof E Solà); Mayo
Clinic College of Medicine and
patient death in the absence of liver transplantation.3–6 deaths due to cirrhosis are highest in Egypt (where the
Science, Rochester, MN, USA
Patients with cirrhosis without any symptoms are termed prevalence of hepatitis C and hepatitis B is very high) and (Prof P S Kamath MD)
to have compensated cirrhosis. Complications such as lowest in Singapore.1 Cirrhosis is the seventh highest Correspondence to:
ascites, variceal bleeding, hepatic encephalopathy, or non- Prof Pere Ginès, Liver Unit,
obstructive jaundice, which can develop with cirrhosis of Hospital Clinic of Barcelona,
any origin, herald the onset of decompensated cirrhosis. In Search strategy and selection criteria Barcelona 08036, Spain
pgines@clinic.cat
the presence of cirrhosis, superimposed hepatic injury We searched the Cochrane Library (from Jan 1, 2010, to
(due to viral, drug-induced, or alcohol-associated hepatitis) March 1, 2021), MEDLINE (from Jan 1, 2000, to March 1, 2021),
or other complications, particularly bacterial infections, can and Embase (from Jan 1, 2008, to March 1, 2021) for
lead to hepatic and extrahepatic organ failure—a condition publications in English exclusively. We used the search terms
known as acute-on-chronic liver failure—that is associated “liver cirrhosis” or “cirrhosis of the liver” in combination with
with high short-term mortality.7 Most deaths in patients “ascites”, “prognosis”, “gastrointestinal bleeding”, “bacterial
with decompensated cirrhosis result from hepatic and infections”, “acute kidney injury”, “hepatic encephalopathy”,
extrahepatic organ failure. Deaths during the compensated “acute-on-chronic liver failure”, “chronic liver diseases”, “liver
stage are largely due to cardiovascular disease, malignancy, disease burden”, “liver fibrosis”, “hepatic fibrosis”,
and renal disease. “compensated cirrhosis”, and “decompensated cirrhosis”.
Cirrhosis appears to receive less public attention than We selected publications mainly from the past 5 years but did
other chronic diseases, such as congestive heart failure, not exclude commonly referenced and highly regarded older
chronic obstructive pulmonary disease, and chronic kidney publications. We also searched the reference lists of articles
disease, which is partly attributable to the stigmatisation of identified by this search strategy and selected those we
cirrhosis and the perception that the disease is largely judged relevant.
related to alcohol consumption.8,9 Public awareness of the
www.thelancet.com Vol 398 October 9, 2021 1359

Downloaded for Anonymous User (n/a) at University of Monterrey from ClinicalKey.com by Elsevier on August 11,
2022. For personal use only. No other uses without permission. Copyright ©2022. Elsevier Inc. All rights reserved.
Seminar
cause of disability-associated life-years in people aged alcohol-related liver disease due to high alcohol
50–74 years, the 12th top cause in the 25–49 age range, consumption (ie, any pattern of alcohol use that is
and the 15th top cause in all ages.11 damaging to health). Approximately 2 billion adults
The most common causes of cirrhosis worldwide are worldwide who are obese or overweight and 400 million
alcohol-related liver disease (also known as alcohol- adults worldwide who have diabetes are also at risk of non-
associated liver disease),12 non-alcoholic fatty liver alcoholic fatty liver disease. The burden of alcohol-related
disease (also known as metabolic-associated fatty liver liver disease and non-alcoholic fatty liver disease is
disease, although this new terminology is not yet predicted to continue to increase in the next few decades.
established),13 and chronic viral hepatitis B and C. Among Cause-specific mortality data are scarce in many
the 2 billion people worldwide who consume any regions where liver disease is highly prevalent, par
amount of alcohol, more than 75 million are at risk of ticularly in Africa. Globally, in 2017, 31·5% of deaths in
male patients with cirrhosis were related to hepatitis B;
25·5% were related to hepatitis C; 27·3% were related to
Panel 1: Aetiology of cirrhosis14 alcohol-related liver disease; 7·7% were associated with
non-alcoholic steatohepatitis, and 8·0% resulted from
Viral other causes.1 Deaths caused by cirrhosis associated
• Hepatitis B* with hepatitis B (24·0%) and alcohol-related liver
• Hepatitis C* disease (20·6%) were lower in women; the proportion
• Hepatitis D (usually superimposed on a hepatitis B related to hepatitis C was similar (26·7%); and the
infection) proportions associated with non-alcoholic fatty liver
Alcohol-related disease (11·3%) and other causes (17·3%) were higher.1
• Alcohol-related liver disease*
Causes and risk factors
Metabolic and genetic The causes of cirrhosis are outlined in panel 1.14 The
• Non-alcoholic fatty liver disease* occurrence of more than one causative factor in a single
• Haemochromatosis patient can lead to more rapid progression to cirrhosis.
• Wilson’s disease Aetiology might also influence the comorbidities
• α1-antitrypsin deficiency associated with cirrhosis: for example, metabolic syn
• Cystic fibrosis drome is more frequent in patients with non-alcoholic
• Lysosomal acid lipase deficiency fatty liver disease.
• Progressive familial intrahepatic cholestasis Table 1 summarises the main risk factors of, and
• Tyrosinaemia type 1 diagnostic methods for, the most common causes of
• Type IV glycogen storage disease cirrhosis. The risk of non-alcoholic fatty liver disease and
Autoimmune alcohol-related liver disease is linked to some genetic risk
• Autoimmune hepatitis variants. Although several single-nucleotide polymorph
• Primary biliary cholangitis isms have been identified,15 the Ile148Met variant of
• Primary sclerosing cholangitis PNPLA3 (rs738409) has the largest effect, increasing the
risk of non-alcoholic fatty liver disease, alcohol-related
Biliary cirrhosis, and hepatocellular carcinoma by two to three
• Biliary atresia times.16,17 A variant in the HSD17B13 gene seems to be
• Biliary strictures protective against these complications.18 Such variants
Vascular might partly explain the vast differences in individual
• Budd-Chiari syndrome susceptibility to alcohol-related and obesity-related liver
• Veno-occlusive disease diseases.19,20 The risk of alcohol-related cirrhosis is closely
• Fontan-associated liver disease associated with drinking patterns,21,22 and increases
• Cardiac cirrhosis substantially with more than three drinks (with one drink
equating to 10 g of pure alcohol) per day. However, up to
Drug-related (long-term use)† 15% of people with such drinking habits have a normal
• Methotrexate liver histology.19 In addition, components of metabolic
• Amiodarone syndrome and alcohol use disorder often coexist and
• Methyldopa constitute a cumulative risk.23,24 Similarly, alcohol overuse
• Vitamin A often overlaps with chronic hepatitis C infection as a risk
Cryptogenic cirrhosis (cause uncertain) factor, and coinfection with hepatitis B and hepatitis C is
estimated to be between 1% and 15%, depending on
*Common causes of cirrhosis. †Long-term not defined because the duration of use that geographical region.25 Among susceptible individuals, the
associates with cirrhosis varies with factors such as obesity and concomitant alcohol
consumption.
risk of progression to cirrhosis and of development of
complications is dependent on several factors, such as
1360 www.thelancet.com Vol 398 October 9, 2021

Seminar
Causative factors Main drivers or contributing Risk of cirrhosis* Primary tests Confirmatory tests† Main differential diagnosis
factors
Metabolism Alcohol consumption Lifestyle 5–10% Alcohol use disorder Urinalysis for ethyl Any other cause mentioned
identification test; blood tests glucuronide‚ liver biopsy, in this table
for γ-glutamyltransferase, and liver elastography‡
aspartate aminotransferase,
alanine aminotransferase, and
mean corpuscular volume; liver
elastography‡
Metabolism Obesity, type 2 Genetic polymorphisms 1–2% Body-mass index, HbA1c, Liver biopsy to detect Any other cause mentioned
diabetes, metabolic (ie, mutations in the PNPLA3 aspartate aminotransferase, non-alcoholic in this table
syndrome gene) and alcohol consumption alanine aminotransferase, steatohepatitis, and liver
fibrosis-4 index, and liver elastography‡
elastography‡
Infection Hepatitis B (90% of Living in high-endemicity Up to 40% if HBsAg testing Presence of hepatitis B Any other cause mentioned
infants and 5–10% of areas (>2% prevalence), including untreated virus DNA in this table
adults infected with the prisons; high-risk sexual
hepatitis B virus behaviours; intravenous drug
develop chronic use; immunosuppressive therapy;
hepatitis) haemodialysis
Infection Hepatitis C (75–80% of Living in high-risk environments 10–20% if untreated Anti-hepatitis C virus antibodies Presence of hepatitis C Any other cause mentioned
all infected patients (eg, prisons); high-risk sexual testing virus RNA in this table
with the hepatitis C behaviours; intravenous drug use;
virus develop chronic immunosuppressive therapy;
hepatitis) haemodialysis; working with
blood products or needles
Genetic Haemochromatosis, ·· 2–4% Serotransferrin (also known as HFE test for Cys282Tyr High alcohol consumption,
predisposition mutations in the HFE transferrin) saturation homozygosity or other metabolic syndrome,
gene >45% (screening test); high HFE genotypes hepatitis B, hepatitis C,
serum ferritin inflammatory states, iron
supplementation, and
frequent blood transfusions
Genetic α-1 antitrypsin ·· 15% with a ZZ Low serum levels of SERPINA1 test for ZZ, SZ, High alcohol consumption,
predisposition deficiency, mutations in genotype for α-1 antitrypsin or MZ genotypes amyloidosis, glycogen
the SERPINA1 gene α-1 antitrypsin storage disease
Genetic Wilson’s disease, ·· Insufficient data Low serum ceruloplasmin Urinary copper in 24 h, Any other cause mentioned
predisposition mutations in the available liver biopsy, genetic in this table
ATP7B gene analysis
Host and Autoimmune hepatitis Female sex (male to female Insufficient data Alanine aminotransferase, IgG, Liver biopsy Non-alcoholic
environmental prevalence ratio: available ANA, smooth muscle antibody, steatohepatitis, hepatitis B,
triggers approximately 1:3) liver-kidney microsomal hepatitis C, primary
antibody, liver cytosolic antigen sclerosing cholangitis,
type 1 primary biliary cholangitis,
Wilson’s disease
Host and Primary biliary Female sex (male to female Approximately 33% Elevation of serum alkaline Serum antimitochondrial Primary sclerosing
environmental cholangitis prevalence ratio: approximately if untreated phosphatase, antibodies, primary cholangitis, secondary
triggers 1:4) γ-glutamyltransferase, biliary cholangitis-specific sclerosing cholangitis,
conjugated bilirubin, or all ANA, normal MRCP, and IgG4-associated cholangitis
liver biopsy§
Host and Primary sclerosing Male sex (male to female Most patients will Elevation of serum alkaline MRCP, liver biopsy§, Secondary sclerosing
environmental cholangitis prevalence ratio: require liver phosphatase and ERCP§ cholangitis
triggers approximately 2:1); two-thirds of transplantation for γ-glutamyltransferase
patients with primary sclerosing complications
cholangitis have concomitant
inflammatory bowel disease
ERCP=endoscopic retrograde cholangiopancreatography. HbA1c=glycated haemoglobin. MRCP=magnetic resonance cholangiopancreatography. *Risk of cirrhosis is defined as the percentage of people in the
population with the corresponding risk factor who will receive a diagnosis of cirrhosis at any time in their life. †To assess the severity of fibrosis, presence of cirrhosis, or portal hypertension, all patients must be
assessed with abdominal ultrasound and elastography. ‡Although useful, liver elastography is not available as primary test in most countries. §Not essential for diagnosis, but can be useful for differential
diagnosis.
Table 1: Aetiology and diagnosis of the most common causes of cirrhosis by risk factor
lifestyle modification (abstinence from alcohol and weight Diagnosis of cirrhosis

loss), vaccination against hepatitis B, control of inflamma The diagnostic evaluation of patients suspected to have
tion (eg, as caused by autoimmune hepatitis and hepatitis cirrhosis depends on the phase of the disease. In patients
B), or eradication of disease (in the case of hepatitis C). with suspected compensated cirrhosis, the aim is to

Seminar
can all be used as first-line screening tests in primary

care to assess hepatic fibrosis. Some non-invasive tests
are commonly used to assess hepatic fibrosis, with
suggested cutoff values being applied to guide clinical
decision making (table 2).38–41 Besides indirect fibrosis
indices, other more direct methods, such as the enhanced
liver fibrosis test and liver elastography, can be used to
assess the degree of hepatic fibrosis.41 Elastography,
which measures the stiffness of the liver, correlates well
with the degree of fibrosis in the fasted state, in the
absence of inflammation, biliary obstruction, and hepatic
congestion.41,42 Transient elastography has been validated
for the assessment of various causes of liver disease41–43
and is the preferred test for its ease of use and utility as a
point-of-care assessment, but is not generally available in
primary care. Hepatic fibrosis can also be assessed by
point shear wave elastography and two-dimensional
shear wave elastography.44 MRI-based methods might be
superior to the aforementioned tests in assessing both
hepatic fibrosis and steatosis, but are more expensive
and less widely available.45,46
Pathophysiology of cirrhosis
The histological structural abnormalities of cirrhosis
lead to a distortion of the hepatic angioarchitecture,
which increases resistance to portal blood and is the
Figure 1: Coronal CT image of the abdomen in a patient with cirrhosis
The liver is shrunken (green cross), shows nodularity (white arrowhead), and is initial factor leading to portal hypertension.47–50 In
surrounded by ascites (green arrowheads). The spleen is enlarged (star). Gastro- addition, an imbalance in the intrahepatic circulation of
oesophageal varices are seen (white arrow). There is a splenorenal shunt between vasoconstrictive and vasodilating agents results in net
a tributary of the splenic vein (green arrow) and the left renal vein (red arrow).
vasoconstriction leading to a dynamic component in
The left renal vein is seen entering the inferior vena cava (curved green arrow).
hepatic resistance that can induce rapid changes in
portal pressure.51 The most thoroughly studied vasoactive
quantify the degree of hepatic fibrosis,19,26,27 assess the agent is nitric oxide. In the cirrhotic liver, the sinusoidal
presence of portal hypertension28 (figure 1), and determine endothelial cells produce less nitric oxide, and this
the cause or causes of the disease (table 1). These factors production might decrease further in response to acute
are strongly associated with the risk of progression and of events such as infections. The ensuing decrease in nitric
subsequent development of complications of cirrhosis, oxide results in further increases in hepatic resistance,
and inform the kind of follow-up required.29 which contributes to increases in portal pressure.52
An assessment of hepatic fibrosis is required to identify The initial increase in portal pressure as a result of
patients at risk of cirrhosis. Liver fibrosis is commonly higher intrahepatic vascular resistance leads to
classified into four stages of increasing severity (figure 2). circulatory abnormalities, the most important of which is
Stage 3 fibrosis and stage 4 fibrosis (which classify as the development of splanchnic arterial vasodilation.53 In
cirrhosis) associate strongly with future liver-associated contrast to what occurs in hepatic circulation, in
morbidity and mortality,26,27,30,31 and thus represent an splanchnic circulation the production of nitric oxide by
important point for timely intervention to prevent further endothelial cells is increased:54 initially as a response to
progression.32,33 vascular shear stress, and later in the disease exacerbated
A liver biopsy is the gold standard for the assessment by bacterial translocation (the passage of viable bacteria
of liver fibrosis. However, the current indication for liver or bacterial products through the gut mucosa to the
biopsy is mainly to determine the cause of liver disease systemic circulation) and by the sustained inflammatory
in selected cases, and not to stage fibrosis. Standard liver response typical of advanced cirrhosis.52–55 Vasodilation in
biochemistry and ultrasonography have low sensitivity the splanchnic capillary beds and arterioles results in an
and specificity (less than 60%) in assessing liver fibrosis increase in portal blood flow that, in combination with an
and are not recommended for this purpose.34,35 However, increase in intrahepatic vascular resistance, results in
several indices combining various markers (ie, panels), increased portal pressure (known as portal hypertension).
such as the Fibrosis-4 Index,36 the Non-Alcoholic Fatty Because the splanchnic vascular bed accounts for about
Liver Disease Fibrosis Score,37 and FibroTest,38 are 25% of the total systemic vascular resistance, progressive
available to assess the degree of fibrosis. These panels splanchnic vasodilation results in a decrease in the

Seminar
Fibrosis Compensated cirrhosis Decompensated cirrhosis
F0 F1 F2 F3 F4 Oesophageal varices
Disease stage Asymptomatic phase Symptomatic phase
Genetic profile Risk factors (eg, alcohol Fibrosis (lifetime risk: Compensated cirrhosis Decompensated cirrhosis ACLF
Natural history of cirrhosis
consumption, excess 10–30%) (lifetime risk: 5–10%)

weight, and viral hepatitis)
Portal hypertension Complications of cirrhosis (eg, ascites, bleeding varices,

Disease progression
infections, jaundice, HE, and HCC)
Endoscopic
Time frame Decades Years Months to years Weeks to months
view
Ultrasonography
Background About 10% at 1 year for patients About 90% at 1 year for patients
Mortality with compensated cirrhosis with advanced ACLF
Liver Ascites
Direct markers of fibrosis Kidney

Clinical signs (eg, jaundice, ascites, spider naevi, caput
Diagnostic tools
ELF <10·5 ELF >10·5 medusae, and oedema)

FibroTest <0·72 FibroTest >0·72
Imaging
Transient elastography CT scan, MRI, and ultrasonography findings (eg, liver nodules,
Transient elastography ascites, enlarged spleen, and portosystemic shunts)
LS <8 kPa LS >12 kPa LS >20–25 kPa
Transient elastography
Treat or eliminate causative factor

Goals of treatment
Liver transplantation when indicated
Prevent fibrosis development Prevent progression of fibrosis Lower portal pressure and Recompensation (ie, stop Reverse organ failure
and progression (ie, stop alcohol (ie, administer ursodeoxycholic prevent complications of alcohol consumption and (ie, administer
consumption, promote weight acid for the traetment of PBC, cirrhosis (ie, administer non- treat hepatitis B and C) terlipressin to treat
loss, and provide anti-hepatitis B prednisolone for AIH, or new selective β blockers) hepatorenal syndrome)
vaccination) agents for NASH)
Figure 2: The clinical spectrum of chronic liver disease

Natural history, diagnostic tools, and goals of treatment according to different stages of chronic liver diseases, from early fibrosis to advanced fibrosis, compensated cirrhosis, and decompensated
cirrhosis. Lifetime risk refers to the lifetime risk of developing cirrhosis. The differently weighted dots in the Goals of treatment panel represent the starting point differences depending on aetiology,
country, and time of diagnosis; no clear consensus exists for early-stage disease approaches. ACLF=acute-on-chronic liver failure. AIH=autoimmune hepatitis. ELF=enhanced liver fibrosis test. F=fibrosis
stage. HCC=hepatocellular carcinoma. HE=hepatic encephalopathy. LS=liver stiffness. NASH=non-alcoholic steatohepatitis. PBC=primary biliary cholangitis.
effective arterial blood volume causing systemic pressure causes a reversal in flow and dilation of pre-
hypotension, arterial underfilling, and activation of existing collateral channels at sites where systemic and
neurohumoral vasoconstrictive systems (ie, sympathetic portal circulation come together (such as at the gastro-
nervous system, renin–angiotensin–aldosterone system, oesophageal junction) and activation of angiogenesis,
and non-osmotic release of vasopressin). These systems which promotes the formation of new collaterals.57 The
aim to counteract vasodilation and lead to sodium and most clinically relevant portosystemic collaterals are
water retention, which results in an increase in plasma gastro-oesophageal varices. When the pressure in these
volume. Part of the excessive plasma volume is varices exceeds the elastic capacity of the vessel wall,
compartmentalised to the peritoneal space as ascites, a variceal bleeding occurs. Portosystemic shunting,
result of portal hypertension. With the progression of together with the deterioration in liver function,
cirrhosis, vasodilation increases and systemic blood contributes to hepatic encephalopathy by decreasing the
pressure progressively decreases, with maximal clearance of gut-derived ammonia.
activation of vasoconstrictors factors. The result is The relevance of portal hypertension in driving
intense vasoconstriction in the renal circulation, complications of cirrhosis has been shown by the close
culminating in hepatorenal syndrome, a form of acute association between the degree of portal hypertension and
kidney injury.56 the risk of complications, and by the decrease in risk that
The increased plasma volume causes an increase results from decreasing portal pressure.58 Arroyo and
in cardiac output, which leads to a hyperdynamic colleagues55 have postulated that the dev elopment
cir
culatory state and, together with splanchnic vaso of systemic inflammation with the progression of cirrhosis
dilation, increases portal blood inflow and perpetuates might have an important role in acute hepatic
portal hypertension (figure 3). The increased portal decompensation. Inflammation is triggered by bacterial

Seminar
Clinical features
Rule out Rule in fibrosis up to Rule in fibrosis
fibrosis if the stage 2 if the value is stage 3 or 4 if Physical findings suggestive of cirrhosis are seen
value is the value is almost exclusively in patients with decompensated
Fibrosis-4 Lower Between 2·67 Higher than disease. The hands can show palmar erythema (red
Index* than 1·3 and 3·25 3·25 coloration of the thenar and hypothenar eminences);
NAFLD Fibrosis Lower Not established Higher than Terry’s nails (a highly specific, but insensitive marker
Score† than –1·455 0·676 of cirrhosis, characterised by proximal nail-bed pallor
FibroTest‡ Lower Between 0·48 Higher than predominantly involving the thumb and index finger);
than 0·31 and 0·72 0·72
and clubbing of the fingernails in case of concomitant
ELF§ Lower Between 9·8 and 10·5 Higher than
hepatopulmonary syndrome. Dupuytren’s contracture,
than 7·7 10·5
which mainly affects the ring and little fingers and
Transient Lower Between 8 kPa and Higher than
elastography than 6 kPa 12 kPa 12 kPa occurs mostly in men older than 60 years and of
northern European descent, is a manifestation of
All markers to rule in fibrosis shown here have a sensitivity of more than 90%. All excessive alcohol consumption rather than of cirrhosis.64
markers to rule out fibrosis shown here have a specificity of more than 90%. Liver
fibrosis is graded into four categories (stage 1 to stage 4), where stage 1 corresponds Other signs of cirrhosis include parotid enlargement,
to mild fibrosis, stage 2 corresponds to substantial fibrosis, and stages 3 and 4 refer especially in patients with alcohol-associated cirrhosis;
to the presence of advanced fibrosis or cirrhosis. NAFLD=non-alcoholic fatty liver scleral icterus; gynecomastia; loss of secondary sexual
disease. ELF=enhanced liver fibrosis test. *The fibrosis-4 index is based on age and
alanine aminotransferase, aspartate aminotransferase, and platelet serum values
characteristics; and spider angiomas visible as a central
and is available as an online calculator.39 †The NAFLD Fibrosis Score is based on age, arteriole with radiating vessels. The exact causes of the
body-mass index, aspartate aminotransferase to alanine aminotransferase ratio, peripheral manifestations of cirrhosis are unclear.
platelets, serum albumin, and presence of diabetes and is available as an online
Some of the vascular manifestations, such as spider
calculator.40 ‡The FibroTest is calculated from α2-macroglobulin, haptoglobin,
apolipoprotein A1, bilirubin and γ-glutamyl transpeptidase values.38 §The ELF is nevi, previously attributed to impaired metabolisation
based on the measurement of amino terminal peptide of type III procollagen, of oestrogens, might be related to an increased
metalloproteinase inhibitor 1, and hyaluronic acid.41 expression of VEGFA.65 Abdominal examination can,
Table 2: Commonly used non-invasive tests to assess the presence of on occasion, show caput medusae (abdominal veins
liver fibrosis and cirrhosis and suggested cutoff values to rule liver distended by blood flow radiating from the umbilicus).
fibrosis out or in In addition, a physical examination can show an
enlarged left hepatic lobe and splenomegaly. The
likelihood of cirrhosis is higher in the presence of
translocation, known to occur frequently in decom ascites (likelihood ratio 7·2 [95% CI 2·9–12·0]) and
pensated cirrhosis. Translocation is facilitated by gut spider nevi (4·3 [2·4–6·2]), and lower in the absence of
bacterial overgrowth, delayed intestinal transit, and an hepatomegaly (0·37 [0·24–0·51]).35 Of note, however, is
increase in gut permeability that occurs in the context of that the liver shrinks with disease progression.
marked changes in gut microbiota composition and Additional clinical findings related to cardiopulmonary,
function.59,60 In the past 10 years, evidence has been neurological, and other complications of cirrhosis are
accumulating to describe the alteration in gut microbiota summarised in table 3.66–87 Patients with decompensated
composition that is seen in cirrhosis, mainly characterised cirrhosis usually die of complications of portal
by loss of genetic diversity, decrease in autochthonous hypertension or of hepatocellular carcinoma.
species, and enrichment with uncommon gut bacteria,
such as Enterococcus spp. Alterations worsen in parallel Portal hypertension and its complications
with cirrhosis progression.60 Although the mechanisms by Ascites
which changes in microbiota composition lead to disease Ascites manifests as an increase in abdominal
progression are not completely elucidated, one hypothesis circumference with abdominal discomfort. Ascites is
is that changes in microbiota composition are associated graded as grade 1 (mild) ascites, which is only detected
with an impairment in microbiota function, leading to on ultrasonography; grade 2 (moderate) ascites,
intestinal inflammation, disruption of intestinal barrier, characterised by moderate abdominal distension,
and increased permeability, aggravating the already discomfort, and shifting dullness; and grade 3 (severe)
existing bacterial translocation. Enrichment by pathogenic ascites, which manifests as tense abdominal distension
species might also contribute to increased endotoxaemia, with a fluid wave.29 Ascites is further classified as
resulting in enhanced systemic inflammation.61 uncomplicated or complicated (ie, recurrent or
Furthermore, whereas the healthy liver acts as a barrier refractory; table 3), the development of which is
between the gut and the systemic circulation,62 cirrhosis associated with poor prognosis (median survival from
disrupts this protection through liver dysfunction and diagnosis 6 months). Therefore, patients with
portosystemic shunting. Portal hypertension, impaired refractory ascites should be evaluated for liver
hepatic function, and the immune dysfunction observed transplantation. Recurrent ascites consists of the
in decompensated cirrhosis63 work in concert to reappearance of grade 2 or grade 3 ascites within
predispose patients with cirrhosis to infection. 4 weeks of initial mobilisation.

Seminar
Complications of cirrhosis
Primary events
Liver dysfunction Hepatic encephalopathy
Cirrhosis
Bacterial translocation,
increased intestinal
permeability, and altered
microbiota composition
Increased intrahepatic
resistance
Vasodilators Portal hypertension Portosystemic collaterals

and increased (ie, varices)
nitric oxide
Vasodilators
Inflammatory
mediators
Immune dysfunction, (IL-6, IL-1, TNF)
Splanchnic vasodilation Increase in blood flow
systemic inflammation
Arterial underfilling, Increased cardiac output

hypotension
Immune dysfunction
(ie, decreased expression
of HLA-DR,and increased
expression of PD-L1) Activation of Sodium and water
neurohumoral retention, and
systems (RAAS, SNS, hypervolaemia
vasopressin)
Bacterial infections Kidney dysfunction Ascites Variceal bleeding
Figure 3: Summary of the pathophysiology of cirrhosis complications

The increase in hepatic resistance (due to structural abnormalities and dynamic changes) leads to an initial increase in portal pressure, resulting in a cascade of
disturbances in the splanchnic and systemic circulation characterised by vasodilation, sodium and water retention, and plasma volume expansion, which have a key
role in causing ascites and hepatorenal syndrome. These alterations also lead to an increase in portal blood inflow, which contributes to maintaining and
aggravating portal hypertension despite the development of collaterals (ie, varices). Collaterals can form into gastrointestinal varices and cause variceal bleeding
and portosystemic shunting that, together with liver dysfunction, cause hepatic encephalopathy. Disease progression is associated with the development of
systemic inflammation that contributes to the impairment of systemic circulatory function through the release of vasodilators. Systemic inflammation is triggered
by bacterial translocation that occurs in the context of increased intestinal permeability and altered microbiota composition. Impaired liver function and immune
dysfunction existing in decompensated cirrhosis lead to higher predisposition to bacterial infections. HLA-DR=human leukocyte antigen-DR isotype. RAAS=renin–
angiotensin–aldosterone system. SNS=sympathetic nervous system.
Portal hypertension-related bleeding hypertension-related gastropathy, enteropathy, or

After ascites, gastrointestinal bleeding is the second colopathy might be more insidious than that from
most common complication in patients with cirrhosis. varices and usually manifests as anaemia.
Variceal bleeding is the most common cause of
bleeding, is overt, and constitutes a medical emergency. Hepatic encephalopathy
Despite improvements in management, variceal Hepatic encephalopathy is defined as the spectrum of
bleeding is associated with a risk of mortality of potentially reversible neuropsychiatric abnor malities
approximately 20% at 6 weeks after onset; mortality is secondary to hepatic dysfunction, portosystemic
even higher in the presence of infection. Prevention shunting, or both,89 and ranges from covert (grades 0 and
and treatment of bacterial infections are associated 1) to overt (grades 2, 3, and 4) hepatic encephalopathy.
with improved survival. The risk of variceal bleeding is Covert hepatic encephalopathy consists of subclinical
mainly related to the size of the varices, but the risk is alterations detectable only by neuropsychological or
further increased by the severity of liver dysfunction electrophysiological testing, and is not evident at physical
and the presence of high-risk red signs on endoscopy. examination.89,90 Despite the absence of clinically evident
Primary prophylaxis (to prevent variceal bleeding) and symptoms, covert hepatic encephalopathy places patients
secondary prophylaxis (to prevent recurrent variceal at risk of motor vehicle accidents91 and is associated
bleeding) are essential to improve the outcomes with a reduced quality of life. Diagnosis is done by
of patients with cirrhosis.88 Bleeding from portal neuropsychological or electrophysiological testing. The

Seminar
easy-to-administer psychometric hepatic encephalopathy ten animals correctly is associated with a high likelihood
score is one of the most widely used tests to diagnose of covert hepatic encephalopathy.
covert hepatic encephalopathy.89,90 In 2017, the animal Overt hepatic encephalopathy comprises grade 2 to
naming test was introduced to appraise impaired grade 4 hepatic encephalopathy and is accompanied by
cognitive function (mainly executive functions) in the clinically detectable neuropsychiatric abnormalities in a
early stages of hepatic encephalopathy.92 In this simple wide severity spectrum. Grade 2 hepatic encephalopathy
semantic fluency test, the patient is asked to identify a is characterised by lethargy or apathy, minimal
series of animals in 60 seconds.92 Identifying less than disorientation for time or place, personality changes,
Definition and diagnostic criteria Treatment Treatment objectives Data sources

Uncomplicated Ascites that can be controlled with sodium Low-sodium diet and diuretics Symptomatic relief of Non-blinded RCT including 440 patients with
ascites restriction and diuretics and that is not (spironolactone, or spironolactone plus ascites and extension of uncomplicated ascites requiring diuretics
associated with infection or AKI furosemide); in patients with tense ascites, survival showing that weekly administration of
large-volume paracentesis with albumin intravenous albumin improved survival at
replacement (6–8 g of albumin per L of ascites 18 months (77% vs 66% with standard of
fluid removed) should be performed; the role care);66 double-blind RCT including
of repeated intravenous albumin 196 patients with ascites on the waiting list
administration to patients with for liver transplantation that compared
uncomplicated ascites is uncertain combination therapy with albumin every
2 weeks and oral midodrine with double
placebo showing no survival differences67
Recurrent or Ascites requiring more than three First-line treatment is large-volume Control of ascites and Meta-analysis showing that TIPS is more
refractory ascites therapeutic paracenteses despite optimal paracentesis with albumin replacement; extension of survival effective than paracentesis in controlling
medical therapy or that cannot be mobilised, TIPS should be considered for suitable ascites;69 in the latest RCT using the current
or the early recurrence of which cannot be candidates (younger than 70 years, preserved standard TIPS technique
prevented because of poor response to liver function with bilirubin <3 mg/dL, no (polytetrafluoroethylene-covered stents),
sodium restriction and diuretic treatment or previous severe encephalopathy, and no heart TIPS improved transplant-free survival
because of diuretic-induced complications that dysfunction); patients must be on intensive compared with paracentesis70
preclude the use of an effective diuretic diuretic therapy (spironolactone 400 mg/day
dosage68 plus furosemide 160 mg/day) for at least
1 week and on a sodium-restricted diet of less
than 88 mEq/day; an absence of response is
characterised by a mean weight loss of up to
0·8 kg over 4 days and by a urinary sodium
output inferior to sodium intake
Hepatic Pleural effusion in the absence of cardiac, Response to diuretic therapy is limited; Symptomatic relief Observational data
hydrothorax pulmonary, or pleural disease thoracocentesis is required for symptom relief;
TIPS can be beneficial for some patients by
providing longer-term relief
Acute variceal Bleeding from dilated portosystemic Cautious transfusion in stable patients after Control of bleeding, RCT showing decreased mortality with
haemorrhage collateral veins at the gastro-oesophageal volume resuscitation (transfusion threshold of prevention of recurrent conservative transfusion;71 meta-analysis
junction due to portal hypertension 7 g/dL); haemostatic treatments include bleeding, extension of showing improved outcomes with a
(bleeding from varices at sites other than the vasoactive treatments (octreotide, survival, and prevention of combination of drugs and endoscopic
oesophagus and stomach is termed ectopic somatostatin, or terlipressin) and endoscopic infections therapy;72 meta-analysis showing that
variceal bleeding) treatment (variceal ligation); rescue TIPS in antibiotic prophylaxis improves survival by
patients with uncontrolled bleeding; preventing infections;73 conflicting results
prophylactic antibiotics (eg, ceftriaxone) from RCTs regarding prevention in patients at
should be given for 7 days or until discharge; high risk of haemorrhage74–76 (benefits
in patients at high risk of recurrent observed in trials including mainly patients
haemorrhage (Child-Turcotte-Pugh B score with alcohol-associated cirrhosis75); for
with active bleeding or Child-Turcotte-Pugh C patients not at high risk, improved outcomes
score 10–13 points), pre-emptive TIPS within with combination therapy versus endoscopic
72 hours of admission improves survival; therapy alone have been observed;77
patients not at high risk can be treated with in patients with refractory ascites, β-blockers
combined β-blockers and variceal ligation should be discontinued if systolic blood
pressure cannot be maintained above
90 mm Hg, or if the patient has kidney
dysfunction or hyponatraemia78
Overt (grades 2–4) Clinically detectable neuropsychiatric Identification and treatment of the trigger can Symptomatic control of Meta-analysis79 and RCT with 299 patients80
hepatic abnormalities control the acute episode in many patients; hepatic encephalopathy showing that oral rifaximin 550 mg twice a
encephalopathy non-absorbable disaccharides (lactulose or day decreased recurrence from 46% to 22%
lactitol) are the first-line treatment for the over a period of 6 months
acute episode and for preventing recurrence;
patients presenting a recurrence of hepatic
encephalopathy on lactulose should be treated
with long-term rifaximin
(Table 3 continues on next page)

Seminar
Definition and diagnostic criteria Treatment Treatment objectives Data sources

(Continued from previous page)
AKI–hepatorenal Cirrhosis with ascites; diagnosis of AKI– First-line therapy for AKI–hepatorenal Reversal of hepatorenal Meta-analysis showing efficacy of terlipressin
syndrome hepatorenal syndrome according to syndrome is terlipressin* plus albumin; syndrome and extension of and albumin in reverting hepatorenal
International Club of Ascites criteria; absence combinations of midodrine, octreotide, and of survival syndrome, but no differences in survival;81
of shock; no response after 2 consecutive albumin, or norepinephrine infusion and midodrine, octreotide, and albumin, or
days of diuretic withdrawal and plasma albumin can also be used norepinephrine and albumin are markedly
volume expansion with albumin (1 g per kg less effective than terlipressin and albumin
of bodyweight); no current or recent use of (on the basis of very scarce evidence)82
nephrotoxic substances (eg, non-steroidal
anti-inflammatory drugs, aminoglycosides,
contrast media); and no macroscopic signs
of structural kidney injury (absence of
proteinuria [>500 mg/dL], absence of
microhaematuria [>50 red blood cells per
high power field], and normal findings on
renal ultrasonography)
SBP The diagnosis of SBP is based on a diagnostic Intravenous antibiotics selected on the basis Control of infection, RCT including 126 patients with SBP showing
paracentesis (ascitic fluid neutrophil count of local experience and risk of multidrug- extension of survival, and that the administration of albumin (1·5 g/kg
>250 cells per μL; the evidence to support the resistant bacteria; intravenous albumin; prevention of recurrent on day 1 and 1 g/kg on day 3) decreases
use of reagent strips for the diagnosis of SBP patients with an episode of SBP should receive SBP mortality (from 29% to 10%);83 the efficacy of
is insufficient); a positive ascitic fluid bacterial antibiotic prophylaxis indefinitely (norfloxacin norfloxacin might be decreasing in recent
culture is not required for the diagnosis of is the first choice) years84
SBP because it is positive in <50% of patients
(nonetheless, ascitic fluid cultures are
recommended to guide antibiotic treatment29)
Bacterial Urinary tract infection, pneumonia, soft Intravenous antibiotics selected on the basis Control of infection and Observational data
infections other tissue infections, and spontaneous of local experience and risk of multidrug- extension of survival
than SBP bacteraemia are among the most common resistant bacteria
infections in cirrhosis; the diagnosis of
infections other than SBP should be based
on the same criteria used in the general
population85
Hepatopulmonary Arterial hypoxaemia in patients with Liver transplantation is the only effective Resolution of Observational data
syndrome cirrhosis and portal hypertension secondary treatment hepatopulmonary
to intrapulmonary vascular dilatation or syndrome
shunting; a contrast echocardiography can
be positive in up to 40% of patients awaiting
liver transplantation, but the gold standard
to show intrapulmonary vascular shunting is
a lung perfusion scan
Portopulmonary Elevated mean pulmonary artery pressure Macitentan reduces mean pulmonary arterial Improvement of mean RCT including 85 patients with
hypertension (>25 mm Hg) at rest in the presence of portal pressure in patients with portopulmonary pulmonary arterial portopulmonary hypertension showing that
hypertension and pulmonary capillary wedge hypertension; other potential therapies pressure; overall macitentan reduces mean pulmonary artery
pressure ≤15 mm Hg; pulmonary include phosphodiesterase type 5 inhibitors, functioning capacity, and pressure;86 no RCTs of ambrisentan exclusively
hypertension is secondary to increased iloprost, and ambrisentan, or liver transplantation eligibility† in patients with portopulmonary
pulmonary vascular resistance (≥3 Wood transplantation† hypertension
units [240 dynes/s per cm⁻⁵])
AKI=acute kidney injury. RCT=randomised controlled trial. SBP=spontaneous bacterial peritonitis. TIPS=transjugular intrahepatic portosystemic shunts. *Terlipressin is not yet available in the USA and Canada.
†Portopulmonary hypertension in itself is not an indication for liver transplantation, but might be a contraindication when mean pulmonary arterial pressure is >35 mm Hg.87 Pharmacological therapy might
improve the transplantability of patients with portopulmonary hypertension. Most patients improve after liver transplantation.
Table 3: Diagnosis, clinical manifestations, and treatment of specific complications of cirrhosis
inappropriate behaviours, construction apraxia, and and readmission to hospital, and greatly affects quality of
asterixis. Somnolence to semi-stupor responsive to life of both patients and caregivers.5
stimuli, confusion, gross disorientation, and bizarre
behaviours are hallmarks of grade 3 hepatic encepha Acute kidney injury and hepatorenal syndrome
lopathy. Grade 4 hepatic encephalopathy corresponds to Acute kidney injury is prevalent in up to 30–50% of
coma, in which the patient is unresponsive to stimuli. hospitalised patients with decompensated cirrhosis56,93
Overt manifestations of hepatic encephalopathy develop and is associated with increased mortality. Acute
in 30–45% of patients with cirrhosis and in 10–50% of kidney injury in cirrhosis is defined as an increase in
patients after placement of a transjugular intrahepatic serum creatinine equal to or greater than 0·3 mg/dL
portosystemic shunt.90 Hepatic encephalopathy is the (≥26·5 μmol/L) within 48 hours, or as percentage
complication that most frequently leads to admission increase in serum creatinine equal to or greater than

Seminar
50% from baseline, known or presumed to have patients might be particularly low due to renal sodium
occurred within the previous 7 days. Acute kidney retention, or high as a consequence of diuretic treatment.
injury is classified into different stages (1A, 1B, 2, or 3) New biomarkers of tubular damage, particularly the iron-
according to the magnitude of the serum creatinine trafficking protein NGAL, can be useful in the differential
increase; stages 2 and 3 are associated with the worst diagnosis of acute kidney injury–hepatorenal syndrome.29,94
prognosis.29
Bacterial infections, diuretic overdose, gastrointestinal Bacterial infections
bleeding, or nephrotoxic drugs (eg, non-steroidal anti- Patients with cirrhosis have a risk of sepsis 2·6 times
inflammatory drugs) are among the most common higher than patients without underlying liver disease.
precipitating factors for acute kidney injury. Patients with The prevalence of bacterial infections in patients admitted
cirrhosis can present with acute kidney injury due to a to hospital because of cirrhosis ranges from 25% to 46%.95,96
variety of causes: prerenal, hepatorenal syndrome, The development of bacterial infections is usually
intrinsic, or postrenal acute kidney injury. Prerenal acute associated with the occurrence of other cirrhosis-related
kidney injury is the most frequent cause of acute kidney complications, such as hepatic encephalopathy or
injury in hospitalised patients with cirrhosis (causing up to gastrointestinal bleeding. Most importantly, bacterial
68% of cases). Patients with decompensated cirrhosis can infections are a frequent cause of hospital readmissions
also present with glomeru lopathies, but intrinsic acute and increase the probability of mortality by four times.63
kidney injury in these patients is mainly due to acute In addition, the development of bacterial infections
tubular necrosis that can be secondary to shock or frequently leads to dysfunction and failure of other organs
nephrotoxicity. Postrenal acute kidney injury in patients in addition to the liver. Bacterial infections are, therefore,
with cirrhosis is quite uncommon. one of the main triggers of acute kidney injury and acute-
Acute kidney injury–hepatorenal syndrome is a unique on-chronic liver failure, and are one of the major
form of functional kidney failure that develops in patients complications and cause of death in these patients.7
with advanced cirrhosis and is frequently associated with Patients with acute-on-chronic liver failure associated
other complications of the disease.56 It has no specific with bacterial infections show worse clinical course and
clinical signs or symptoms, but is characterised by a higher mortality at 90 days than patients with acute-on-
marked reduction in renal blood flow leading to a reduction chronic liver failure without bacterial infections.97
in glomerular filtration rate, and arterial hypotension is a Together with urinary tract infection, spontaneous
common finding. After the definition of acute kidney bacterial peritonitis is the most common type of infection
injury in cirrhosis was revised, in 2015, the terms type 1 in patients with cirrhosis, followed by pneumonia, skin
and type 2 hepatorenal syndrome are no longer used, with and soft tissue infections, and spontaneous bacteraemia
type 1 hepatorenal syndrome now called acute kidney (table 3).
injury–hepatorenal syndrome, and type 2 hepatorenal Spontaneous bacterial peritonitis is defined as a bacterial
syndrome classed as not meeting the criteria for acute infection of the ascitic fluid, without any identifiable,
kidney injury (non-acute renal injury–hepatorenal intra-abdominal, surgically treatable source of infection.63
syndrome). Non-acute kidney injury is further subdivided Clinical presentation of spontaneous bacterial peritonitis
into acute kidney disease–hepatorenal syndrome if the is very heterogeneous and manifestations include
estimated glomerular filtration rate is less than 60 mL/min abdominal pain, vomiting, diarrhoea, and non-specific
per 1·73 m² for less than 3 months, or chronic kidney symptoms; it can also be asymptomatic. A diagnostic
disease–hepatorenal syndrome if the estimated glomerular paracentesis should be done for all patients hospitalised
filtration rate is less than 60 mL/min per 1·73 m² for more for cirrhosis with ascites or other complications of
than 3 months. Chronic kidney disease–hepatorenal cirrhosis to rule out the presence of spontaneous bacterial
syndrome is increasingly common in patients with non- peritonitis. Neutrophil count and ascitic fluid culture in
alcoholic fatty liver disease-related cirrhosis. blood culture bottles should also be done (table 3).
Although bacterial infection is the most frequent Although early diagnosis and appropriate management
precipitating factor, acute kidney injury–hepatorenal has improved the prognosis of spontaneous bacterial
syndrome can also occur without any identifiable peritonitis over the years, in-hospital mortality remains at
precipitating factor.56 There are no laboratory tests or approximately 20%.29
markers specific for the diagnosis of acute kidney injury– Of note, patients with cirrhosis who have bacterial
hepatorenal syndrome, the diagnosis of which is made infections other than spontaneous bacterial peritonitis
only after ruling out other causes of acute kidney injury can present with only some of the following features:
and confirming the absence of markers of intrinsic acute signs of systemic inflammation (ie, fever, high white
kidney injury, such as haematuria, proteinuria, or kidney blood cell count, high C-reactive protein, and tachycardia);
abnormalities on ultrasonography (table 3). Classic worsening liver function; hepatic encephalopathy; acute
biomarkers such as urine sodium, fractional excretion of kidney injury; gastrointestinal bleeding; or shock.
sodium, or urine osmolality have limitations in patients Bacterial infections should be ruled out in all patients
with cirrhosis and ascites because urine sodium in these presenting with complications of cirrhosis or worsening

Seminar
of liver or kidney function. Health care-associated or the severity of cirrhosis (from 10% in patients with
nosocomial spontaneous bacterial peritonitis carries a compensated cirrhosis to 26% in patients considered
high risk of infection with multidrug-resistant bacteria. candidates for transplantation).108 Cirrhosis results in a
decrease in both procoagulant and anticoagulant factors,
Acute-on-chronic liver failure together with an increase in coagulation factor VIII
Acute-on-chronic liver failure occurs in approximately and von Willebrand factor.109 Therefore, patients with
30% of patients hospitalised for cirrhosis and is advanced cirrhosis are frequently in a prothrombotic state
associated with a grave prognosis.98,99 There is wide that, together with the decrease in the portal vein flow
variation in the definitions of acute-on-chronic liver velocity characteristic of cirrhosis, might facilitate portal
failure across different continents, probably because of vein thrombosis. Although, theoretically, portal vein
disagreement regarding whether it is a distinct syndrome thrombosis might increase portal pressure and thus the
or a terminal stage in all patients with cirrhosis. However, risk of complications, whether portal vein thrombosis
there is broad agreement that acute-on-chronic liver contributes to decompensation or is just a manifestation
failure is a syndrome characterised by acute decom of a more advanced stage of the disease is still unclear.110
pensation of cirrhosis associated with rapid deterioration Anticoagulation therapy increases the chances of portal
in the condition of the patient due to the development of vein recanalisation,111 but the benefits of anticoagulation
multiple organ failure. Given the poor prognosis in these are unclear for patients other than those on the waiting
patients, there is an urgent need to harmonise the list for transplantation, for whom extensive portal vein
definition of acute-on-chronic liver failure worldwide to thrombosis might pose a challenge to a successful
facilitate studies on effective management. In most transplantation.
patients with acute-on-chronic liver failure, a precipitating
factor that varies depending on geographical region Management of liver cirrhosis
can be identified. Bacterial infections and alcohol General considerations
consumption are the most frequent precipitating factors After cirrhosis is confirmed in a patient, the goal of
in Europe and the USA; exacerbation of or superimposed management is to reverse the cause of the disease
viral hepatitis is an additional risk factor in Asia.100 In whenever possible, delay hepatic decompensation, carry
some patients, no precipitating factor can be identified. out surveillance for hepatocellular carcinoma and
oesophageal varices, manage complications, determine
Frailty and sarcopenia the prognosis, and assess suitability for liver
Malnutrition and, consequently, sarcopenia and physical transplantation.
frailty parallel the severity of cirrhosis. Both adipose tissue The aim of the initial laboratory evaluation in all patients
and muscle mass can be depleted in these patients. with cirrhosis includes determining the aetiology (table 1).
Malnutrition is present in more than 50% of patients with Ultrasonography, including doppler ultrasound, is the
decompensated cirrhosis and is associated with a higher initial imaging modality used for patients with suspected
probability of other complications, such as bacterial cirrhosis; direct or indirect signs detected by ultrasound
infections and hepatic encephalopathy, and with increased can help to confirm the diagnosis. The presence of
mortality.101,102 Considering its high frequency and weight splenomegaly, portosystemic collaterals, and ascites on
on prognosis, nutritional and sarcopenia screening is ultrasonography are indicative of portal hypertension and
recommended for all patients with decompensated of high risk of progression to decompensated cirrhosis.28
cirrhosis and in patients at high risk of malnutrition. A Patients with cirrhosis must undergo endoscopic
body-mass index of less than 18·5 kg/m² and advanced surveillance for gastro-oesophageal varices to identify can
cirrhosis (class C in the Child-Turcotte-Pugh score) are didates to primary prophylaxis against variceal bleeding.
factors predictive of malnutrition and sarcopenia.103,104 However, in patients with A-score cirrhosis on the Child-
Handgrip strength is recommended as an easy-to- Turcotte-Pugh score, liver stiffness on transient
measure, inexpensive, and effective point-of-care tool to elastography (<20 kPa), and normal platelet count (or even
assess malnutrition and frailty in patients with cirrhosis.105 transient elastography of <25 kPa and platelet count
Patients with cirrhosis have an increased prevalence of >110 000/mm³), the likelihood of having oesophageal
obesity than the general population, but reduced muscle varices requiring treatment is very low and endoscopy
mass and frailty can still occur in these patients in can be avoided.88,112,113 Patients with large varices should
parallel with the progression of the liver disease. be treated with β-blockers (eg, nadolol, propranolol, or
Therefore, a combination of obesity, sarcopenia, and carvedilol) or repeated endoscopic variceal band ligation.88
frailty, which has been defined as sarcopenic obesity, can In a randomised controlled trial including 201 patients
coexist in patients with cirrhosis.105–107 with compensated cirrhosis who had clinically significant
portal hypertension, non-selective β-blockers decreased
Portal vein thrombosis the risk of decompensation (from 27% to 17% over a
Cirrhosis is associated with an increased risk of portal median follow-up of 37 months) mostly by decreasing the
vein thrombosis, the prevalence of which increases with risk of ascites.114 The trial selected patients on the basis of

Seminar
hepatic venous pressure gradient measurements, which is show any benefit over the standard of care. Detailing the
not feasible in clinical practice. However, developments in specific management of each complication would fall
non-invasive tests over the past 10 years (figure 2) might beyond the scope of this Seminar, and a summary is
allow the non-invasive diagnosis of clinically significant presented in table 3. Thus far, no available therapies
portal hypertension, which could lead to early initiation of other than treating the direct cause have an effect on the
β-blockers. overall course of decompensated cirrhosis, and the
Non-invasive markers of fibrosis and transient development of disease-modifying agents is still an area
elastography should not be used in the evaluation of of research. Liver transplantation is the definitive
patients with decompensated cirrhosis and cannot be therapy for patients with decompensated cirrhosis and
used to exclude the need for surveillance endoscopy, should be considered when the expected survival with
which is mandatory in the decompensated phase. All transplantation is better than that without. On that
patients with ascites require a diagnostic paracentesis to basis, patients with decompensated cirrhosis or a Model
assess for spontaneous bacterial peritonitis and rule out for End-Stage Liver Disease (MELD) score of 15 points
non-cirrhotic causes of ascites.29 or more should be considered for liver transplantation.120
The daily energy intake in patients who are not obese
should be 35 kcal/kg, including a daily protein intake Prognosis and disease scores
1·2–1·5 g/kg, along with vitamin and zinc sup Patients with cirrhosis can be broadly classified as
plementation as required. Advising small and frequent having compensated cirrhosis (with a low risk of
high-calorie meals along with a bedtime snack is the mortality) or decompensated cirrhosis (with a higher
easiest way to achieve this goal.105 Aerobic and resistance risk of mortality). When compared with the general
exercises with emphasis on balance and flexibility should population, patients with compensated cirrhosis have a
be emphasised.115 Patients with cirrhosis from any cause 5 times increased risk of death, whereas patients with
should abstain from alcohol and be advised on smoking decompensated cirrhosis have a 10 times increased risk.
cessation. Patients with compensated cirrhosis have a median
Immunisation against hepatitis A virus, hepatitis B survival of 9–12 years from diagnosis,3,121 which falls to
virus, pneumococcal pneumonia, and influenza should 2 years with the onset of hepatic decompensation.122 In a
be administered to all patients with cirrhosis. If analgesic large population-based study in Denmark, which
drugs are required, paracetamol in doses of up to 2 g included about 15 000 patients with predominantly
daily can be safely used in patients with cirrhosis, but alcohol-associated cirrhosis, the probability of survival
non-steroidal anti-inflammatory drugs should be avoided in patients with cirrhosis was 66% at 1 year, 38% at
(especially in patients with decom pensated cirrhosis) 5 years, and 22% at 10 years.123 The survival rate at 1 year
because they can precipitate acute kidney injury.116 ACE in patients with compensated cirrhosis was 83%,
inhibitors and angiotensin receptor blockers can cause dropping to 80% with variceal bleeding, 71% with
hypotension and kidney failure in patients with ascites ascites, 51% in the presence of both ascites and variceal
and should also be avoided. Statins are safe for patients bleeding, and 36% with hepatic encephalopathy. The
with compensated cirrhosis, but should be used with annual risk of decompensation varies with disease
caution and at low doses because of the risk of aetiology and is 4% for patients with hepatitis C-related
rhabdomyolysis.117 cirrhosis, 6–10% in those with alcohol-associated
Treatment of the cause should be considered for cirrhosis (higher with continued drinking), and 10% for
patients with cirrhosis at any stage because reversing the patients with hepatitis B-related cirrhosis.123 The risk of
cause of the disease is associated with a lower risk decompensation is associated with low serum albumin
of hepatic decompensation and increased chances of concentrations, increasing MELD score, and increased
achieving recompensation.29 Weight loss, which is the portal pressure.14
mainstay of treatment of non-alcoholic fatty liver disease, Survival depends not only on the severity of liver
can have a beneficial effect in patients with obesity and disease but also on the presence of comorbidities. As the
cirrhosis of any cause.118 population with cirrhosis ages and the prevalence of
cirrhosis secondary to non-alcoholic fatty liver disease
Management of decompensated cirrhosis increases, cardiovascular disease, malignancy, diabetes,
The treatment of decompensated cirrhosis is directed sarcopenia, and frailty are expected to become major
at each specific complication, which frequently presents factors contributing to negative outcomes. Portal
in combination with others. Challenging this concept, pressure as measured by an hepatic venous pressure
a recent randomised controlled trial assessed if gradient is associated with hepatic decompensation and
20% albumin infusions could improve the prognosis mortality risk, but the invasive nature and expense of the
(risk of infection, kidney dysfunction, or death) of procedure make repeated measurements impractical.124
777 patients hospitalised for decompensated cirrhosis Simple numeric scores that can be calculated at the
with any complication of the disease and serum albumin bedside can be used to gauge mortality risk. The Child-
below 30 g/L.119 Repeated albumin infusions did not Turcotte-Pugh score uses serum albumin, bilirubin,

Seminar
prothrombin time, and the subjectively assessed hepatocellular carcinoma.133 Hepatic resection or tumour
parameters of ascites and hepatic encephalopathy to ablation might be carried out for very early-stage
broadly classify patients into classes A, B, and C.125 hepatocellular carcinoma (stage 0 on this system),
Patients in class A generally have compensated cirrhosis whereas liver transplantation is recommended for
and are at low risk of mortality; such patients can early-stage disease (stage A). Patients with intermediate
undergo surgical procedures with a low risk of mortality. (stage B) disease might benefit from radiology-guided
The MELD score uses the objective variables of serum regional therapy. Immune-based therapies, including
bilirubin, international normalised ratio, and serum the combination of atezolizumab and bevacizumab, are
creatinine126 to calculate a score ranging between 6 used for patients in the advanced stage (stage C).134
and 40. The higher the MELD score, the greater is the Recent data suggest that patients with non-viral
risk of mortality; for example, patients with a MELD hepatocellular carcinoma (particularly non-alcoholic
score of 40 are unlikely to survive for more than 3 months steatohepatitis-related hepatocellular carcinoma) might
without liver transplantation. Patients with a MELD be less responsive to immunotherapy.135 Patients with
score of up to 12 are at very low risk of mortality at terminal (Barcelona Clinic Liver Cancer stage D)
3 months, even with major surgical procedures.127 The disease (class C on the Child-Turcotte-Pugh score or
MELD-Na score includes serum sodium, which is an poor performance status) receive only supportive care.
independent predictor of mortality, as a variable.128 The
MELD-Na score is used in several parts of the world to Challenges and controversies
prioritise allocation of organs for liver transplantation. Role of nurses in patient care
The relationship between MELD and MELD-Na scores The improvements in nursing care for the management
and mortality can be determined by entering variables of patients with chronic conditions, such as diabetes,
at the respective publicly available websites.129,130 MELD arterial hypertension, heart failure, and lung diseases in
scores can underestimate mortality risk in patients with the past 20 years have not been accompanied by similar
acute-on-chronic liver failure, especially in the presence developments in the field of liver diseases.136 The need to
of circulatory or respiratory failure, in patients with engage nurses in the care of patients with cirrhosis has
hepatocellular carcinoma, and in patients with been identified as a priority by the Lancet Standing
complications such as hepatopulmonary syndrome and Commission on Liver Disease in the UK and by the
portopulmonary hypertension. LiverHope Nursing Project.137,138 Cirrhosis constitutes an
ideal area for innovations in nursing care because of the
Hepatocellular carcinoma characteristics and long natural history of the disease.
Hepatocellular carcinoma accounts for about 90% of all The care of patients with cirrhosis includes both
primary liver cancers and, every year, 1–4% of patients community-based care and hospital care. Therefore,
with cirrhosis will develop hepatocellular carcinoma.14 nurses not only provide a continuum of care but also
Infection with hepatitis B (in sub-Saharan Africa and facilitate patient education and responsibility for their
southeast Asia) and hepatitis C viruses (in the USA, own care, including through the application of
Europe, and Japan) is the most important risk factor innovative technologies such as telehealth and remote
for the development of hepatocellular carcinoma, monitoring, helping patients to make informed
although non-alcoholic fatty liver disease is an decisions and achieve self-care to prevent complications
increasingly recognised risk factor for hepatocellular and improve their wellbeing. Nurses in the community
carcinoma that can develop in the absence of cirrhosis.131 can also have a key role in early diagnosis of the disease,
Evidence of the association between metabolic syndrome, by identifying individuals at high risk of cirrhosis
diabetes, obesity, and hepatocellular carcinoma is also from among at-risk populations using diagnostic
accumulating.132 algorithms or advanced technologies, such as transient
In patients with cirrhosis, surveillance for hepatocellular elastography.139 Future directions include specific
carcinoma is recommended every 6 months through education of nurses involved in the care of patients with
ultrasonography. Lesions with 1 cm or more in diameter cirrhosis in these and in telehealth and remote
on ultrasonography are followed up by either quadruple- monitoring technologies, a training that should be
phase CT or dynamic contrast-enhanced MRI. On provided by scientific societies, universities, or nurse
contrast imaging, hepatocellular carcinoma is brighter organisations. Specific activities that could be included
than the surrounding liver in the arterial phase (which in the proposed role of nurses in the care of patients
is called arterial enhancement) and darker than the with cirrhosis are shown in panel 2.
surrounding parenchyma in the venous and delayed
phases (so-called delayed washout) with a sensitivity of Outstanding research questions
89% and a specificity of 96% for the diagnosis of Although the outcome of complications of cirrhosis
hepatocellular carcinoma. (such as variceal bleeding, spontaneous bacterial
The Barcelona Clinic Liver Cancer staging system is peritonitis, and acute kidney injury–hepatorenal
widely used for the staging and management of syndrome) has improved as a result of intensive research

Seminar
in these areas, many other relevant research questions can be used for long-term therapy to reduce complications
remain. For example, a very important area of research is of portal hypertension (particularly refractory ascites or
the relationship between alterations in the intestinal recurrent variceal bleeding) has been growing.144
microbiome and translocation of bacteria and bacterial Although aetiology-specific therapies exist for most
products and hepatic and systemic inflammation and causes of cirrhosis (eg, antiviral drugs for cirrhosis
progression of cirrhosis.59,140,141 In this regard, some induced by hepatitis C or hepatitis B) and can be used
studies suggest the potential benefits of statin treatment even in decompensated cirrhosis, there is no
aimed at reducing systemic inflammation in patients pharmacological therapy for patients with non-alcoholic
with cirrhosis.142,143 In the past 10 years, interest in the fatty liver disease, which has become the second most
development of specific splanchnic vasoconstrictors that common cause of cirrhosis in many countries.29 Acute-
on-chronic liver failure is the most frequent cause of
death in patients with decompensated cirrhosis, and
Panel 2: Proposed nursing care of patients with cirrhosis there is no effective therapy besides liver transplantation,
according to disease stage which is not always possible and not widely available,
particularly in low-income countries. Exciting experi
Patients with compensated cirrhosis mental data indicate that liver organoids that retain most
• Counselling and health education about specific causes of human liver cell functions and improve survival when
the disease (eg, obesity and alcohol consumption) transplanted to animals with liver failure can be
• Counselling on physical activity and nutrition engineered.145 Finally, the issue of reversibility of cirrhosis
• Identification of patients for screening for gastro- is another important area of investigation. Although
oesophageal varices and hepatocellular carcinoma reversibility of cirrhosis and hepatic fibrosis has been
• Nursing education of patients and caregivers regarding reported sporadically in compensated cirrhosis after
complications and early detection of cirrhosis, including elimination of the cause,146 the reversibility of cirrhosis in
alarm signs patients with decompensated disease still represents a
• Regular follow-up with standard visits or telehealth major research challenge. Other important areas that
Patients with decompensated cirrhosis require improvement include a multidisciplinary
All of the above, accompanied by: approach to alcohol overuse, diagnosis and management
• Control of specific complications, particularly ascites and of nutrition and sarcopenia, and palliative care. Other
hepatic encephalopathy relevant open issues regarding the management of
• Support of compliance with medications complications in patients with decompensated cirrhosis
• Regular assessment of quality of life and frailty indexes are summarised in panel 3.
• Identification of patients suitable for liver transplantation
• Remote monitoring and telehealth visits Clinical trials in cirrhosis
• Palliative care for terminally ill patients There is a paucity of well conducted clinical trials
evaluating new or repurposed therapies for patients with
decompensated cirrhosis. Many published therapeutic
trials in cirrhosis are underpowered, have poorly defined
Panel 3: Some clinically relevant questions regarding the populations, and evaluate soft clinical endpoints. Trials
management of complications in patients with should be done in well defined populations of patients
decompensated cirrhosis with advanced (ie, decompensated) cirrhosis, include a
• Does transjugular intrahepatic portosystemic shunt sufficient sample size, and use hard clinical endpoints,
improve survival in patients with diuretic-responsive particularly transplant-free survival or combined end
ascites without increasing the incidence of hepatic points of complications and patient-reported outcomes.147
encephalopathy? Specifically, the outcomes should reflect improvements
• Is long-term albumin administration effective in in quality of life, in reducing or eliminating symptoms,
decreasing complications and improving survival of and in enabling patients to have a healthy social and
patients with cirrhosis and ascites? working life.
• Is refractory ascites a contraindication for the use of
β blockers in prevention of variceal bleeding? Clinical guidelines from scientific societies
• Is prophylactic quinolone administration for the prevention Of the several clinical guidelines for the management of
of spontaneous bacterial peritonitis associated with an complications of cirrhosis published in the past 5 years,
increased risk of infection by multidrug-resistant bacteria? the most relevant are those from international hepatology
• Are any of the treatments for complications such as societies (eg, the European Association for the Study of
variceal bleeding, ascites, and hepatic encephalopathy the Liver29 and the American Association for the Study of
also associated with better quality of life and improved Liver Diseases)148 and from the Baveno Consensus
functioning in the community? Workshops.88 In the future, guideline task force groups
should ideally be co-organised by transcontinental

Seminar
societies to ensure that recommendations can be 5 Fabrellas N, Moreira R, Carol M, et al. Psychological burden of
universally adopted. hepatic encephalopathy on patients and caregivers.
Clin Transl Gastroenterol 2020; 11: e00159.
6 Allen AM, Kim WR, Moriarty JP, Shah ND, Larson JJ, Kamath PS.
Cirrhosis as major public health problem Time trends in the health care burden and mortality of acute on
The importance of liver diseases in general—and chronic liver failure in the United States. Hepatology 2016;
64: 2165–72.
cirrhosis specifically—as major health issues has been 7 Arroyo V, Moreau R, Jalan R. Acute-on-chronic liver failure.
largely underestimated. For example, the term liver N Engl J Med 2020; 382: 2137–45.
disease does not appear in the WHO list of non- 8 Vaughn-Sandler V, Sherman C, Aronsohn A, Volk ML.
Consequences of perceived stigma among patients with cirrhosis.
communicable diseases that includes, among others, Dig Dis Sci 2014; 59: 681–86.
cardiovascular diseases, cerebrovascular diseases, dia 9 Burnham B, Wallington S, Jillson IA, et al. Knowledge, attitudes,
betes, and chronic respiratory diseases.149 This lack of and beliefs of patients with chronic liver disease. Am J Health Behav
appropriate consideration is likely to be a contributory 2014; 38: 737–44.
10 Asrani SK, Devarbhavi H, Eaton J, Kamath PS. Burden of liver
factor to the low awareness of liver diseases, both at the diseases in the world. J Hepatol 2019; 70: 151–71.
public and health professional levels, and to the scarcity 11 Vos T, Lim SS, Abbafati C, et al. Global burden of 369 diseases and
of appropriate campaigns against liver diseases. Efforts injuries in 204 countries and territories, 1990–2019: a systematic
analysis for the Global Burden of Disease Study 2019. Lancet 2020;
should be made at the national and international scales 396: 1204–22.
to place liver diseases at the level required to counteract 12 Crabb DW, Im GY, Szabo G, Mellinger JL, Lucey MR. Diagnosis and
the stigmatisation of the disease and initiate campaigns treatment of alcohol-associated liver diseases: 2019 practice
guidance from the American Association for the Study of Liver
to promote liver health. Diseases. Hepatology 2020; 71: 306–33.
Contributors 13 Eslam M, Sanyal AJ, George J, et al. MAFLD: a consensus-driven
All authors contributed equally to the writing and reviewing of proposed nomenclature for metabolic associated fatty liver disease.
different sections of the Seminar and approved the final version for Gastroenterology 2020; 158: 1999–2014.
submission. 14 Kamath PS, Shah V. Overview of cirrhosis. In: Qayed E,
Shahnavaz N, eds. Sleisenger and Fordtran’s gastrointestinal and
Declaration of interests liver disease: review and assessment, 11th edn. Philadelphia, PA:
PG reports research funding from Gilead Sciences, Mallinckrodt Elsevier, 2020: 1164–71.
Pharmaceuticals, and Grifols; and participation in advisory boards for 15 Emdin CA, Haas M, Ajmera V, et al. Association of genetic variation
Gilead Sciences, Grifols, Mallinckrodt, Novartis, Martin with cirrhosis: a multi-trait genome-wide association and gene-
Pharmaceuticals, and Ferring. AK is a speaker and advisory board environment interaction study. Gastroenterology 2020; 160: 1620–33.
member for Norgine and Siemens. JGA is a consultant for Gilead 16 Carlsson B, Lindén D, Brolén G, et al. Review article: the emerging
Sciences, Intercept, Genfit, Lupin, Inventiva, and Boehringer Ingelheim; role of genetics in precision medicine for patients with
and reports grant support from Gilead Sciences and speaker fees from non-alcoholic steatohepatitis. Aliment Pharmacol Ther 2020;
Lupin. NF participated in advisory boards for Intercept. PSK is an 51: 1305–20.
advisory board member of Sequana. ES declares no competing interests. 17 Stickel F, Moreno C, Hampe J, Morgan MY. The genetics of alcohol
dependence and alcohol-related liver disease. J Hepatol 2017;
Acknowledgments 66: 195–211.
We dedicate this work to the memories of Prof Juan Rodés and
18 Abul-Husn NS, Cheng X, Li AH, et al. A protein-truncating
Robert W Schier. PG is supported by the grants LiverHope 731875 and HSD17B13 variant and protection from chronic liver disease.
LiverScreen 847989 (European Commission Horizon 2020), N Engl J Med 2018; 378: 1096–106.
FIS PI20/00579 (integrated in the Plan Nacional I+D+I and co-funded by 19 Parker R, Aithal GP, Becker U, et al. Natural history of histologically
ISCIII-Subdirección General de Evaluación and European Regional proven alcohol-related liver disease: a systematic review. J Hepatol
Development Fund), by Centro de Investigación Biomédica en Red de 2019; 71: 586–93.
Enfermedades Hepáticas y Digestivas, and by the Agency for 20 Younossi ZM, Koenig AB, Abdelatif D, Fazel Y, Henry L, Wymer M.
Management of University and Research Grant grant number AGAUR Global epidemiology of nonalcoholic fatty liver disease—
2017_SGR_01281. NF is supported by the grant FIS 18/01330 (integrated meta-analytic assessment of prevalence, incidence, and outcomes.
in the Plan Nacional I+D+I and co-funded by ISCIII-Subdirección Hepatology 2016; 64: 73–84.
General de Evaluación and European Regional Development Fund). 21 Wood AM, Kaptoge S, Butterworth AS, et al. Risk thresholds for
PSK is partly supported by the National Institutes of Health’s National alcohol consumption: combined analysis of individual-participant
Institute on Alcohol Abuse and Alcoholism grant U01AA26974. data for 599 912 current drinkers in 83 prospective studies. Lancet
We acknowledge the support of Nicki van Berckel and Roser Poblet in 2018; 391: 1513–23.
the preparation of this Seminar and the expert technical assistance of 22 Simpson RF, Hermon C, Liu B, et al. Alcohol drinking patterns and
Stine Johansen in drawing figure 2. liver cirrhosis risk: analysis of the prospective UK Million Women
Study. Lancet Public Health 2019; 4: e41–48.
References 23 Israelsen M, Juel HB, Detlefsen S, et al. Metabolic and genetic risk
1 Sepanlou SG, Safiri S, Bisignano C, et al. The global, regional, factors are the strongest predictors of severity of alcohol-related
and national burden of cirrhosis by cause in 195 countries and liver fibrosis. Clin Gastroenterol Hepatol 2020; published online
territories, 1990–2017: a systematic analysis for the Global Burden Dec 4. https://doi.org/10.1016/j.cgh.2020.11.038.
of Disease Study 2017. Lancet Gastroenterol Hepatol 2020;
24 Pose E, Pera G, Torán P, et al. Interaction between metabolic
5: 245–66.
syndrome and alcohol consumption, risk factors of liver fibrosis:
2 Pellicoro A, Ramachandran P, Iredale JP, Fallowfield JA. Liver a population-based study. Liver Int 2021; 41: 1556–64.
fibrosis and repair: immune regulation of wound healing in a solid
25 Mavilia MG, Wu GY. HBV-HCV coinfection: viral interactions,
organ. Nat Rev Immunol 2014; 14: 181–94.
management, and viral reactivation. J Clin Transl Hepatol 2018;
3 D’Amico G, Garcia-Tsao G, Pagliaro L. Natural history and 6: 296–305.
prognostic indicators of survival in cirrhosis: a systematic review of
26 Hagström H, Thiele M, Roelstraete B, Söderling J, Ludvigsson JF.
118 studies. J Hepatol 2006; 44: 217–31.
Mortality in biopsy-proven alcohol-related liver disease:
4 Solà E, Watson H, Graupera I, et al. Factors related to quality of life a population-based nationwide cohort study of 3453 patients. Gut
in patients with cirrhosis and ascites: relevance of serum sodium 2021; 70: 170–79.
concentration and leg edema. J Hepatol 2012; 57: 1199–206.

Seminar
27 Taylor RS, Taylor RJ, Bayliss S, et al. Association between fibrosis 51 Bhathal PS, Grossman HJ. Reduction of the increased portal
stage and outcomes of patients with nonalcoholic fatty liver disease: vascular resistance of the isolated perfused cirrhotic rat liver by
a systematic review and meta-analysis. Gastroenterology 2020; vasodilators. J Hepatol 1985; 1: 325–37.
158: 1611–25. 52 Wiest R, Groszmann RJ. The paradox of nitric oxide in cirrhosis
28 D’Amico G, Morabito A, D’Amico M, et al. Clinical states of and portal hypertension: too much, not enough. Hepatology 2002;
cirrhosis and competing risks. J Hepatol 2018; 68: 563–76. 35: 478–91.
29 Angeli P, Bernardi M, Villanueva C, et al. EASL Clinical Practice 53 McAvoy NC, Semple S, Richards JMJ, et al. Differential visceral
Guidelines for the management of patients with decompensated blood flow in the hyperdynamic circulation of patients with liver
cirrhosis. J Hepatol 2018; 69: 406–60. cirrhosis. Aliment Pharmacol Ther 2016; 43: 947–54.
30 Simon TG, Roelstraete B, Khalili H, Hagstrom H, Ludvigsson JF. 54 Martin PY, Ginès P, Schrier RW. Nitric oxide as a mediator of
Mortality in biopsy-confirmed nonalcoholic fatty liver disease: hemodynamic abnormalities and sodium and water retention in
results from a nationwide cohort. Gut 2020; 70: 1375–82. cirrhosis. N Engl J Med 1998; 339: 533–41.
31 Hagström H, Nasr P, Ekstedt M, et al. Fibrosis stage but not NASH 55 Arroyo V, Angeli P, Moreau R, et al. The systemic inflammation
predicts mortality and time to development of severe liver disease in hypothesis: towards a new paradigm of acute decompensation and
biopsy-proven NAFLD. J Hepatol 2017; 67: 1265–73. multiorgan failure in cirrhosis. J Hepatol 2021; 74: 670–85.
32 Spearman CW, Dusheiko GM, Hellard M, Sonderup M. 56 Ginès P, Solà E, Angeli P, Wong F, Nadim MK, Kamath PS.
Hepatitis C. Lancet 2019; 394: 1451–66. Hepatorenal syndrome. Nat Rev Dis Primers 2018; 4: 23.
33 Seto WK, Lo YR, Pawlotsky JM, Yuen MF. Chronic hepatitis B virus 57 Fernández M, Semela D, Bruix J, Colle I, Pinzani M, Bosch J.
infection. Lancet 2018; 392: 2313–24. Angiogenesis in liver disease. J Hepatol 2009; 50: 604–20.
34 Zheng J, Guo H, Zeng J, et al. Two-dimensional shear-wave 58 Abraldes JG, Tarantino I, Turnes J, Garcia-Pagan JC, Rodés J,
elastography and conventional US: the optimal evaluation of liver Bosch J. Hemodynamic response to pharmacological treatment of
fibrosis and cirrhosis. Radiology 2015; 275: 290–300. portal hypertension and long-term prognosis of cirrhosis.
35 Udell JA, Wang CS, Tinmouth J, et al. Does this patient with liver Hepatology 2003; 37: 902–08.
disease have cirrhosis? JAMA 2012; 307: 832–42. 59 Acharya C, Bajaj JS. Chronic liver diseases and the microbiome-
36 Tapper EB, Lok AS. Use of liver imaging and biopsy in clinical translating our knowledge of gut microbiota to management of
practice. N Engl J Med 2017; 377: 756–68. chronic liver disease. Gastroenterology 2021; 160: 556–72.
37 Angulo P, Hui JM, Marchesini G, et al. The NAFLD fibrosis score: 60 Solé C, Guilly S, Da Silva K, et al. Alterations in gut microbiome in
a noninvasive system that identifies liver fibrosis in patients with cirrhosis as assessed by quantitative metagenomics: relationship
NAFLD. Hepatology 2007; 45: 846–54. with acute-on-chronic liver failure and prognosis. Gastroenterology
38 Munteanu M, Pais R, Peta V, et al. Long-term prognostic value of 2021; 160: 206–18.
the FibroTest in patients with non-alcoholic fatty liver disease, 61 Bajaj JS, Heuman DM, Hylemon PB, et al. Altered profile of human
compared to chronic hepatitis C, B, and alcoholic liver disease. gut microbiome is associated with cirrhosis and its complications.
Aliment Pharmacol Ther 2018; 48: 1117–27. J Hepatol 2014; 60: 940–47.
39 Sterling R. Fibrosis-4 (FIB-4) index for liver fibrosis. https://www. 62 Balmer ML, Slack E, de Gottardi A, et al. The liver may act as a
mdcalc.com/fibrosis-4-fib-4-index-liver-fibrosis (accessed firewall mediating mutualism between the host and its gut
July 26, 2021). commensal microbiota. Sci Transl Med 2014; 6: 237ra66.
40 Sterling R. NAFLD (Non-Alcoholic Fatty Liver Disease) Fibrosis 63 Jalan R, Fernandez J, Wiest R, et al. Bacterial infections in cirrhosis:
Score. https://www.mdcalc.com/nafld-non-alcoholic-fatty-liver- a position statement based on the EASL Special Conference 2013.
disease-fibrosis-score (accessed July 26, 2021). J Hepatol 2014; 60: 1310–24.
41 Thiele M, Madsen BS, Hansen JF, Detlefsen S, Antonsen S, Krag A. 64 Attali P, Ink O, Pelletier G, et al. Dupuytren’s contracture, alcohol
Accuracy of the enhanced liver fibrosis test vs FibroTest, consumption, and chronic liver disease. Arch Intern Med 1987;
elastography, and indirect markers in detection of advanced fibrosis 147: 1065–67.
in patients with alcoholic liver disease. Gastroenterology 2018; 65 Li CP, Lee FY, Hwang SJ, et al. Spider angiomas in patients with
154: 1369–79. liver cirrhosis: role of vascular endothelial growth factor and
42 Eddowes PJ, Sasso M, Allison M, et al. Accuracy of FibroScan basic fibroblast growth factor. World J Gastroenterol 2003;
controlled attenuation parameter and liver stiffness measurement 9: 2832–35.
in assessing steatosis and fibrosis in patients with nonalcoholic 66 Caraceni P, Riggio O, Angeli P, et al. Long-term albumin
fatty liver disease. Gastroenterology 2019; 156: 1717–30. administration in decompensated cirrhosis (ANSWER): an open-
43 Papatheodoridi M, Hiriart JB, Lupsor-Platon M, et al. Refining the label randomised trial. Lancet 2018; 391: 2417–29.
Baveno VI elastography criteria for the definition of compensated 67 Sola E, Solé C, Simon-Talero M, et al. Midodrine and albumin for
advanced chronic liver disease. J Hepatol 2020; 74: 1109–16. prevention of complications of cirrhosis in patients in the waiting
44 Herrmann E, de Lédinghen V, Cassinotto C, et al. Assessment of list for liver transplantation. A randomized, multicenter, double-
biopsy-proven liver fibrosis by two-dimensional shear wave blind, placebo-controlled trial. J Hepatol 2018; 69: 1250–59.
elastography: an individual patient data-based meta-analysis. 68 Arroyo V, Ginès P, Gerbes AL, et al. Definition and diagnostic
Hepatology 2018; 67: 260–72. criteria of refractory ascites and hepatorenal syndrome in cirrhosis.
45 Imajo K, Honda Y, Kobayashi T, et al. Direct comparison of US and International Ascites Club. Hepatology 1996; 23: 164–76.
MR elastography for staging liver fibrosis in patients with 69 D’Amico G, Luca A, Morabito A, Miraglia R, D’Amico M.
nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol 2020; Uncovered transjugular intrahepatic portosystemic shunt for
published online Dec 17. refractory ascites: a meta-analysis. Gastroenterology 2005;
46 Park CC, Nguyen P, Hernandez C, et al. Magnetic resonance 129: 1282–93.
elastography vs transient elastography in detection of fibrosis and 70 Bureau C, Thabut D, Oberti F, et al. Transjugular intrahepatic
noninvasive measurement of steatosis in patients with biopsy- portosystemic shunts with covered stents increase transplant-free
proven nonalcoholic fatty liver disease. Gastroenterology 2017; survival of patients with cirrhosis and recurrent ascites.
152: 598–607. Gastroenterology 2017; 152: 157–63.
47 Wanless IR. The role of vascular injury and congestion in the 71 Villanueva C, Colomo A, Bosch A, et al. Transfusion strategies for
pathogenesis of cirrhosis: the congestive escalator and the acute upper gastrointestinal bleeding. N Engl J Med 2013;
parenchymal extinction sequence. Curr Hepatol Rep 2020; 19: 40–53. 368: 11–21.
48 Tschumperlin DJ, Ligresti G, Hilscher MB, Shah VH. 72 Wells M, Chande N, Adams P, et al. Meta-analysis: vasoactive
Mechanosensing and fibrosis. J Clin Invest 2018; 128: 74–84. medications for the management of acute variceal bleeds.
49 Trautwein C, Friedman SL, Schuppan D, Pinzani M. Hepatic Aliment Pharmacol Ther 2012; 35: 1267–78.
fibrosis: Concept to treatment. J Hepatol 2015; 62 (suppl): S15–24. 73 Sanchez-Jimenez B, Chavez-Tapia NC, Jakobsen JC, Nikolova D,
50 Ramachandran P, Dobie R, Wilson-Kanamori JR, et al. Resolving Gluud C. Antibiotic prophylaxis versus placebo or no intervention
the fibrotic niche of human liver cirrhosis at single-cell level. Nature for people with cirrhosis and variceal bleeding.
2019; 575: 512–18. Cochrane Database Syst Rev 2018; 11: CD013175.

Seminar
74 Dunne PDJ, Sinha R, Stanley AJ, et al. Randomised clinical trial: 95 Piano S, Singh V, Caraceni P, et al. Epidemiology and effects of
standard of care versus early-transjugular intrahepatic porto- bacterial infections in patients with cirrhosis worldwide.
systemic shunt (TIPSS) in patients with cirrhosis and oesophageal Gastroenterology 2019; 156: 1368–80.
variceal bleeding. Aliment Pharmacol Ther 2020; 52: 98–106. 96 Piano S, Brocca A, Mareso S, Angeli P. Infections complicating
75 García-Pagán JC, Caca K, Bureau C, et al. Early use of TIPS in cirrhosis. Liver Int 2018; 38 (suppl 1): 126–33.
patients with cirrhosis and variceal bleeding. N Engl J Med 2010; 97 Fernández J, Acevedo J, Wiest R, et al. Bacterial and fungal
362: 2370–79. infections in acute-on-chronic liver failure: prevalence,
76 Lv Y, Yang Z, Liu L, et al. Early TIPS with covered stents versus characteristics and impact on prognosis. Gut 2018; 67: 1870–80.
standard treatment for acute variceal bleeding in patients with 98 Moreau R, Jalan R, Gines P, et al. Acute-on-chronic liver failure is a
advanced cirrhosis: a randomised controlled trial. distinct syndrome that develops in patients with acute
Lancet Gastroenterol Hepatol 2019; 4: 587–98. decompensation of cirrhosis. Gastroenterology 2013; 144: 1426–37.
77 Albillos A, Zamora J, Martínez J, et al. Stratifying risk in the 99 Piano S, Tonon M, Vettore E, et al. Incidence, predictors and
prevention of recurrent variceal hemorrhage: results of an outcomes of acute-on-chronic liver failure in outpatients with
individual patient meta-analysis. Hepatology 2017; 66: 1219–31. cirrhosis. J Hepatol 2017; 67: 1177–84.
78 Garcia-Tsao G, Abraldes JG, Berzigotti A, Bosch J. Portal hypertensive 100 Shi Y, Yang Y, Hu Y, et al. Acute-on-chronic liver failure precipitated
bleeding in cirrhosis: risk stratification, diagnosis, and management: by hepatic injury is distinct from that precipitated by extrahepatic
2016 practice guidance by the American Association for the Study of insults. Hepatology 2015; 62: 232–42.
Liver Diseases. Hepatology 2017; 65: 310–35. 101 Gunsar F, Raimondo ML, Jones S, et al. Nutritional status and
79 Gluud LL, Vilstrup H, Morgan MY. Non-absorbable disaccharides prognosis in cirrhotic patients. Aliment Pharmacol Ther 2006;
versus placebo/no intervention and lactulose versus lactitol for the 24: 563–72.
prevention and treatment of hepatic encephalopathy in people with 102 Montano-Loza AJ, Meza-Junco J, Prado CMM, et al. Muscle wasting
cirrhosis. Cochrane Database Syst Rev 2016; 4: CD003044. is associated with mortality in patients with cirrhosis.
80 Bass NM, Mullen KD, Sanyal A, et al. Rifaximin treatment in Clin Gastroenterol Hepatol 2012; 10: 166–73.
hepatic encephalopathy. N Engl J Med 2010; 362: 1071–81. 103 Cederholm T, Bosaeus I, Barazzoni R, et al. Diagnostic criteria for
81 Best LM, Freeman SC, Sutton AJ, et al. Treatment for hepatorenal malnutrition—an ESPEN Consensus Statement. Clin Nutr 2015;
syndrome in people with decompensated liver cirrhosis: a network 34: 335–40.
meta-analysis. Cochrane Database Syst Rev 2019; 9: CD013103. 104 Tandon P, Ney M, Irwin I, et al. Severe muscle depletion in patients
82 Cavallin M, Kamath PS, Merli M, et al. Terlipressin plus albumin on the liver transplant wait list: its prevalence and independent
versus midodrine and octreotide plus albumin in the treatment of prognostic value. Liver Transpl 2012; 18: 1209–16.
hepatorenal syndrome: a randomized trial. Hepatology 2015; 105 Merli M, Berzigotti A, Zelber-Sagi S, et al. EASL Clinical Practice
62: 567–74. Guidelines on nutrition in chronic liver disease. J Hepatol 2019;
83 Sort P, Navasa M, Arroyo V, et al. Effect of intravenous albumin on 70: 172–93.
renal impairment and mortality in patients with cirrhosis and 106 Montano-Loza AJ, Angulo P, Meza-Junco J, et al. Sarcopenic obesity
spontaneous bacterial peritonitis. N Engl J Med 1999; 341: 403–09. and myosteatosis are associated with higher mortality in patients
84 Mücke MM, Mücke VT, Graf C, et al. Efficacy of norfloxacin with cirrhosis. J Cachexia Sarcopenia Muscle 2016; 7: 126–35.
prophylaxis to prevent spontaneous bacterial peritonitis: a systematic 107 Nishikawa H, Nishiguchi S. Sarcopenia and sarcopenic obesity are
review and meta-analysis. Clin Transl Gastroenterol 2020; 11: e00223. prognostic factors for overall survival in patients with cirrhosis.
85 Horan TC, Andrus M, Dudeck MA. CDC/NHSN surveillance Intern Med 2016; 55: 855–56.
definition of health care-associated infection and criteria for specific 108 Senzolo M, Garcia-Tsao G, García-Pagán JC. Current knowledge
types of infections in the acute care setting. Am J Infect Control and management of portal vein thrombosis in cirrhosis. J Hepatol
2008; 36: 309–32. 2021; 75: 442–53.
86 Sitbon O, Bosch J, Cottreel E, et al. Macitentan for the treatment of 109 Tripodi A, Primignani M, Mannucci PM, Caldwell SH. Changing
portopulmonary hypertension (PORTICO): a multicentre, concepts of cirrhotic coagulopathy. Am J Gastroenterol 2017;
randomised, double-blind, placebo-controlled, phase 4 trial. 112: 274–81.
Lancet Respir Med 2019; 7: 594–604.
110 Nery F, Chevret S, Condat B, et al. Causes and consequences of
87 Krowka MJ, Fallon MB, Kawut SM, et al. International Liver portal vein thrombosis in 1,243 patients with cirrhosis: results of a
Transplant Society practice guidelines: diagnosis and management longitudinal study. Hepatology 2015; 61: 660–67.
of hepatopulmonary syndrome and portopulmonary hypertension.
111 Loffredo L, Pastori D, Farcomeni A, Violi F. Effects of
Transplantation 2016; 100: 1440–52.
anticoagulants in patients with cirrhosis and portal vein
88 de Franchis R, Baveno VIF. Expanding consensus in portal thrombosis: a systematic review and meta-analysis. Gastroenterology
hypertension: report of the Baveno VI Consensus Workshop: 2017; 153: 480–87.
stratifying risk and individualizing care for portal hypertension.
112 Petta S, Sebastiani G, Bugianesi E, et al. Non-invasive prediction of
J Hepatol 2015; 63: 743–52.
esophageal varices by stiffness and platelet in non-alcoholic fatty
89 American Association for the Study of Liver Diseases. Hepatic liver disease cirrhosis. J Hepatol 2018; 69: 878–85.
encephalopathy in chronic liver disease: 2014 practice guideline by
113 Augustin S, Pons M, Maurice JB, et al. Expanding the Baveno VI
the European Association for the Study of the Liver and the
criteria for the screening of varices in patients with compensated
American Association for the Study of Liver Diseases. J Hepatol
advanced chronic liver disease. Hepatology 2017; 66: 1980–88.
2014; 61: 642–59.
114 Villanueva C, Albillos A, Genescà J, et al. β blockers to prevent
90 Rose CF, Amodio P, Bajaj JS, et al. Hepatic encephalopathy: novel
decompensation of cirrhosis in patients with clinically significant
insights into classification, pathophysiology and therapy. J Hepatol
portal hypertension (PREDESCI): a randomised, double-blind,
2020; 73: 1526–47.
placebo-controlled, multicentre trial. Lancet 2019; 393: 1597–608.
91 Bajaj JS, Hafeezullah M, Hoffmann RG, et al. Navigation skill
115 Tandon P, Ismond KP, Riess K, et al. Exercise in cirrhosis:
impairment: another dimension of the driving difficulties in
translating evidence and experience to practice. J Hepatol 2018;
minimal hepatic encephalopathy. Hepatology 2008; 47: 596–604.
69: 1164–77.
92 Campagna F, Montagnese S, Ridola L, et al. The animal naming
116 Elia C, Graupera I, Barreto R, et al. Severe acute kidney injury
test: an easy tool for the assessment of hepatic encephalopathy.
associated with non-steroidal anti-inflammatory drugs in cirrhosis:
Hepatology 2017; 66: 198–208.
a case-control study. J Hepatol 2015; 63: 593–600.
93 Huelin P, Piano S, Solà E, et al. Validation of a staging system for
117 Bosch J, Gracia-Sancho J, Abraldes JG. Cirrhosis as new indication
acute kidney injury in patients with cirrhosis and association with
for statins. Gut 2020; 69: 953–62.
acute-on-chronic liver failure. Clin Gastroenterol Hepatol 2017;
15: 438–445. 118 Berzigotti A, Albillos A, Villanueva C, et al. Effects of an intensive
lifestyle intervention program on portal hypertension in patients
94 Huelin P, Solà E, Elia C, et al. Neutrophil gelatinase-associated
with cirrhosis and obesity: the SportDiet study. Hepatology 2017;
lipocalin for assessment of acute kidney injury in cirrhosis:
65: 1293–305.
a prospective study. Hepatology 2019; 70: 319–33.

Seminar
119 China L, Freemantle N, Forrest E, et al. A randomized trial of 135 Pfister D, Núñez NG, Pinyol R, et al. NASH limits anti-tumour
albumin infusions in hospitalized patients with cirrhosis. surveillance in immunotherapy-treated HCC. Nature 2021;
N Engl J Med 2021; 384: 808–17. 592: 450–56.
120 Merion RM, Schaubel DE, Dykstra DM, Freeman RB, Port FK, 136 Fabrellas N, Carol M, Torrabadella F, de Prada G. Nursing care of
Wolfe RA. The survival benefit of liver transplantation. patients with chronic liver diseases: time for action. J Adv Nurs
Am J Transplant 2005; 5: 307–13. 2018; 74: 498–500.
121 Ginés P, Quintero E, Arroyo V, et al. Compensated cirrhosis: 137 Williams R, Ashton K, Aspinall R, et al. Implementation of the
natural history and prognostic factors. Hepatology 1987; 7: 122–28. Lancet Standing Commission on Liver Disease in the UK. Lancet
122 Llach J, Ginès P, Arroyo V, et al. Prognostic value of arterial 2015; 386: 2098–111.
pressure, endogenous vasoactive systems, and renal function in 138 Fabrellas N, Carol M, Palacio E, et al. Nursing care of patients with
cirrhotic patients admitted to the hospital for the treatment of cirrhosis: the LiverHope Nursing Project. Hepatology 2020;
ascites. Gastroenterology 1988; 94: 482–87. 71: 1106–16.
123 Jepsen P, Vilstrup H, Andersen PK, Lash TL, Sørensen HT. 139 Fabrellas N, Alemany M, Urquizu M, et al. Using transient
Comorbidity and survival of Danish cirrhosis patients: elastography to detect chronic liver diseases in a primary care nurse
a nationwide population-based cohort study. Hepatology 2008; consultancy. Nurs Res 2013; 62: 450–54.
48: 214–20. 140 Albillos A, de Gottardi A, Rescigno M. The gut-liver axis in liver
124 Ripoll C, Groszmann R, Garcia-Tsao G, et al. Hepatic venous disease: pathophysiological basis for therapy. J Hepatol 2020;
pressure gradient predicts clinical decompensation in patients with 72: 558–77.
compensated cirrhosis. Gastroenterology 2007; 133: 481–88. 141 Trebicka J, Bork P, Krag A, Arumugam M. Utilizing the gut
125 Pugh RN, Murray-Lyon IM, Dawson JL, Pietroni MC, Williams R. microbiome in decompensated cirrhosis and acute-on-chronic liver
Transection of the oesophagus for bleeding oesophageal varices. failure. Nat Rev Gastroenterol Hepatol 2021; 18: 167–80.
Br J Surg 1973; 60: 646–49. 142 Abraldes JG, Villanueva C, Aracil C, et al. Addition of simvastatin to
126 Kamath PS, Wiesner RH, Malinchoc M, et al. A model to predict standard therapy for the prevention of variceal rebleeding does not
survival in patients with end-stage liver disease. Hepatology 2001; reduce rebleeding but increases survival in patients with cirrhosis.
33: 464–70. Gastroenterology 2016; 150: 1160–70.e3.
127 Northup PG, Friedman LS, Kamath PS. AGA clinical practice 143 Pose E, Trebicka J, Mookerjee RP, Angeli P, Ginès P. Statins:
update on surgical risk assessment and perioperative management old drugs as new therapy for liver diseases? J Hepatol 2019;
in cirrhosis: expert review. Clin Gastroenterol Hepatol 2019; 70: 194–202.
17: 595–606. 144 Fernández-Varo G, Oró D, Cable EE, et al. Vasopressin 1a receptor
128 Kim WR, Biggins SW, Kremers WK, et al. Hyponatremia and partial agonism increases sodium excretion and reduces portal
mortality among patients on the liver-transplant waiting list. hypertension and ascites in cirrhotic rats. Hepatology 2016; 63: 207–16.
N Engl J Med 2008; 359: 1018–26. 145 Hu H, Gehart H, Artegiani B, et al. Long-term expansion of
129 Kamath PS. MELD Score (Model For End-Stage Liver Disease) functional mouse and human hepatocytes as 3D organoids.
(12 and older). https://www.mdcalc.com/meld-score-model-end- Cell 2018; 175: 1591–606.
stage-liver-disease-12-older (accessed July 26, 2021). 146 Hytiroglou P, Theise ND. Regression of human cirrhosis:
130 Kim WR. MELDNa/MELDNa score for liver cirrhosis. https://www. an update, 18 years after the pioneering article by Wanless et al.
mdcalc.com/meldna-meld-na-score-liver-cirrhosis (accessed Virchows Arch 2018; 473: 15–22.
July 26, 2021). 147 Solà E, Pose E, Campion D, et al. Endpoints and design of clinical
131 Llovet JM, Kelley RK, Villanueva A, et al. Hepatocellular carcinoma. trials in patients with decompensated cirrhosis: position paper of
Nat Rev Dis Primers 2021; 7: 6. the LiverHope Consortium. J Hepatol 2021; 74: 200–19.
132 Forner A, Reig M, Bruix J. Hepatocellular carcinoma. Lancet 2018; 148 Biggins S, Angeli P, Garcia-Tsao G, et al. Diagnosis, evaluation, and
391: 1301–14. management of ascites and hepatorenal syndrome. Hepatology 2021;
133 Llovet JM, De Baere T, Kulik L, et al. Locoregional therapies in the published online May 3. https://doi.org/10.1002/hep.31884.
era of molecular and immune treatments for hepatocellular 149 WHO. Noncommunicable diseases. April 13, 2021. https://www.
carcinoma. Nat Rev Gastroenterol Hepatol 2021; 18: 293–313. who.int/news-room/fact-sheets/detail/noncommunicable-diseases
134 Finn RS, Qin S, Ikeda M, et al. Atezolizumab plus bevacizumab in (accessed July 26, 2021).
unresectable hepatocellular carcinoma. N Engl J Med 2020;
382: 1894–905. © 2021 Elsevier Ltd. All rights reserved.


Liver Cirrhosis Pere Gines

Uploaded by

Copyright:

Available Formats

Liver Cirrhosis Pere Gines

Uploaded by

Document Information

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Liver Cirrhosis Pere Gines

Uploaded by

Copyright:

Available Formats

Seminar

www.thelancet.com Vol 398 October 9, 2021 1359

1360 www.thelancet.com Vol 398 October 9, 2021

lifestyle modification (abstinence from alcohol and weight Diagnosis of cirrhosis

www.thelancet.com Vol 398 October 9, 2021 1361

can all be used as first-line screening tests in primary

1362 www.thelancet.com Vol 398 October 9, 2021

Fibrosis Compensated cirrhosis Decompensated cirrhosis

consumption, excess 10–30%) (lifetime risk: 5–10%)

Portal hypertension Complications of cirrhosis (eg, ascites, bleeding varices,

Direct markers of fibrosis Kidney

ELF <10·5 ELF >10·5 medusae, and oedema)

Treat or eliminate causative factor

Liver transplantation when indicated

Figure 2: The clinical spectrum of chronic liver disease

www.thelancet.com Vol 398 October 9, 2021 1363

1364 www.thelancet.com Vol 398 October 9, 2021

Liver dysfunction Hepatic encephalopathy

Vasodilators Portal hypertension Portosystemic collaterals

Arterial underfilling, Increased cardiac output

Bacterial infections Kidney dysfunction Ascites Variceal bleeding

Figure 3: Summary of the pathophysiology of cirrhosis complications

Portal hypertension-related bleeding hypertension-related gastropathy, enteropathy, or

www.thelancet.com Vol 398 October 9, 2021 1365

Definition and diagnostic criteria Treatment Treatment objectives Data sources

1366 www.thelancet.com Vol 398 October 9, 2021

Definition and diagnostic criteria Treatment Treatment objectives Data sources

Table 3: Diagnosis, clinical manifestations, and treatment of specific complications of cirrhosis

www.thelancet.com Vol 398 October 9, 2021 1367

1368 www.thelancet.com Vol 398 October 9, 2021

www.thelancet.com Vol 398 October 9, 2021 1369

1370 www.thelancet.com Vol 398 October 9, 2021

www.thelancet.com Vol 398 October 9, 2021 1371

1372 www.thelancet.com Vol 398 October 9, 2021

www.thelancet.com Vol 398 October 9, 2021 1373

1374 www.thelancet.com Vol 398 October 9, 2021

www.thelancet.com Vol 398 October 9, 2021 1375

1376 www.thelancet.com Vol 398 October 9, 2021

You might also like