Liver cirrhosis: Ancient disease, new challenge

Abstract

Liver cirrhosis is a common cause of morbidity and mortality worldwide. Excessive alcohol consumption and metabolic associated steatotic liver disease are the most common etiological factors of cirrhosis in our region. Cirrhosis occurs in two well-differentiated phases, compensated and decompensated, depending on the absence or presence of complications, respectively. Current therapeutic strategies are aimed at controlling these complications (such as ascites, hepatic encephalopathy, bacterial infections, or digestive hemorrhage, among others) or performing a liver transplant if there are no contraindications. However, it is important to eliminate the etiological factor responsible for the disease, as this can lead to the disappearance of complications, a state known as recompensation. This article proposes an updated review of the epidemiology of cirrhosis and its main causes, and offers an overview of the clinical features and treatment of the disease's complications, in addition to outlining future lines of research in this field.

Resumen

La cirrosis hepática es una causa muy frecuente de morbilidad y mortalidad en todo el mundo. Los factores etiológicos más frecuentes de cirrosis en nuestro medio son el consumo excesivo de alcohol y la enfermedad hepática por depósito de grasa de origen metabólico. La cirrosis se presenta en dos fases bien diferenciades, compensada y descompensada, según la ausencia o presencia de complicaciones asociadas, respectivamente. Las estrategias terapéuticas actuales se dirigen al control de las complicaciones (ascitis, encefalopatía hepática, infecciones bacterianas o hemorragia digestiva, entre otras) o a la realización de un trasplante hepático si no existen contraindicaciones; no obstante, es importante conseguir la eliminación del factor etiológico responsable de la enfermedad, puesto que ello puede conducir a la desaparición de las complicaciones, estado que se denomina recompensación. El presente artículo propone una revisión actualizada sobre la epidemiología de la cirrosis y sus principales causas, y ofrece una visión general de la clínica y tratamiento de las complicaciones de la enfermedad, además de trazar las futuras líneas de investigación en este campo.

Introduction

Cirrhosis of the liver represents the end stage of a large proportion of chronic liver diseases and is now a common cause of morbidity and mortality worldwide.¹

It is clinically characterised by two distinct stages. A first asymptomatic phase in which patients have no complications of the disease, known as compensated cirrhosis, and a second phase in which specific symptoms and complications develop, known as decompensated cirrhosis. In this symptomatic phase, patients develop recurrent complications that lead to a deterioration in quality of life.¹

There is currently no curative treatment for cirrhosis, although removing the aetiological factor of cirrhosis can sometimes lead to the resolution of episodes of decompensation. This phenomenon is known as recompensation.²

The current management of patients with cirrhosis is based on the specific treatment of complications, with liver transplantation being the only treatment capable of altering the natural history of the disease.¹

This review summarises the current knowledge on the causes of cirrhosis, the mechanisms involved in disease progression and decompensation, and the strategy for diagnostic and therapeutic approach to these patients.

Epidemiology

Liver cirrhosis represents the end stage of chronic liver disease and is a major cause of morbidity and mortality in most countries of the world.¹ It causes morbidity and mortality mainly through the development of clinical complications (ascites, hepatic encephalopathy [HE], bacterial infections, gastrointestinal bleeding or hepatocellular carcinoma). Cirrhosis-associated mortality accounts for 2.4% of mortality worldwide, and is responsible for approximately two million deaths annually, ranking as the eleventh leading cause of death globally.^3,4 The health impact of cirrhosis is particularly high in the young adult population, with the 25–49 age group being most affected by the disease.⁵

Worldwide, the most common cause of cirrhosis-associated mortality is hepatitis C, followed by alcohol, hepatitis B and metabolic dysfunction-associated steatotic liver disease (MASLD), respectively.⁶ However, in Europe, heavy alcohol consumption is by far the most common cause of morbidity and mortality associated with cirrhosis. The high prevalence of alcohol-induced liver disease is compounded by the fact that it affects a significantly younger population compared to other chronic diseases such as diabetes. This fact determines that chronic liver diseases and in particular cirrhosis is the second cause of loss of working life years in Europe after ischaemic heart disease, representing a major health impact of liver cirrhosis.⁷

Aetiology and pathogenesis

The causes of cirrhosis have changed significantly in recent years. Hepatitis C, which used to be the main cause, has decreased dramatically with the introduction of direct-acting antivirals (DAAs).⁸ Alcohol consumption is currently the leading cause in Spain, closely followed by metabolic liver disease.⁴ It is important to note that some patients may have more than one aetiological factor coexisting, which may accelerate disease progression. The main causes of cirrhosis are set out in detail in Table 1.¹

Table 1.

Aetiology of cirrhosis.

Viral

Hepatitis C

Hepatitis B

Hepatitis D (overlapping hepatitis B)

Alcohol-related

Alcohol-related liver disease

Metabolic and genetic

Metabolic liver disease

Haemochromatosis

Wilson's disease

Alpha-1 antitrypsin deficiency

Cystic fibrosis

Lysosomal acid lipase deficiency

Progressive familial intrahepatic cholestasis

Tyrosinaemia type 1

Glycogen storage disease type IV

Autoimmune

Autoimmune hepatitis

Primary biliary cholangitis

Primary sclerosing cholangitis

Biliary

Biliary atresia

Biliary stenosis

Vascular

Budd-Chiari syndrome

Veno-occlusive disease

Fontan-associated chronic liver disease

Cardiac cirrhosis

Drug-related (long-term use)

Methotrexate

Amiodarone

Methyldopa

Vitamin A

Cryptogenic cirrhosis (uncertain cause)

Adapted from Ref.¹.

Alcohol-associated liver disease

Alcohol consumption carries a substantial risk of cirrhosis, which is closely linked to drinking patterns: the risk increases significantly after the intake of more than two standard drinks (SDs) of alcohol per day, corresponding to approximately 20 g of pure alcohol, and is lower for women.⁹ The risk of developing cirrhosis increases with the amount and duration of alcohol consumption. The prognosis for patients with decompensated cirrhosis who continue to drink alcohol is poor. On the other hand, in patients with cirrhosis who abstain from alcohol, it is common to observe a recompensation of the disease after a long period of abstinence, and this situation can be maintained for a long time.^10,11

Metabolic liver disease

The diagnosis of MASLD is established by the presence of hepatic steatosis and the identification of cardiometabolic risk factors, in addition to the absence of other aetiologies of chronic liver disease.¹² With disease progression and the development of cirrhosis, the characteristic histological signs of MASLD, such as steatosis and liver inflammation, may disappear. In these cases, the diagnosis should be established according to the presence of cardiometabolic risk factors and the absence of other aetiological factors in a patient with liver cirrhosis.

Recently, the nomenclature of liver diseases that present with steatosis has been modified, such as alcohol-related liver disease or metabolic liver disease.¹² Both entities fall within the spectrum of steatotic liver disease (SLD). This new definition aims to provide a positive nomenclature for metabolic fatty liver disease, rather than as a precursor to alcohol consumption (previously referred to as non-alcoholic fatty liver disease), and to remove the term "fatty", which has a stigmatising and pejorative connotation. In addition, the concept of mixed disease associated with alcohol consumption and the presence of cardiometabolic risk factors has been introduced in this new definition. This entity has been named MetALD.¹²

Viral hepatitis

Liver cirrhosis caused by hepatitis C virus (HCV) currently has a residual incidence in our environment.⁸ It follows long-term chronic HCV infection; approximately half of the patients have a history of blood transfusion prior to 1989 or parenteral drug exposure.¹³ The diagnosis is established by the detection of serological markers such as anti-HCV antibody (anti-HCV) and HCV-RNA.¹³

Hepatitis B virus (HBV) infection is the leading cause of chronic liver disease globally, especially in Asia and Africa.¹⁴ Although in Spain the prevalence of HBV infection is moderate and universal vaccination has reduced its incidence, migration from high prevalence territories has compensated for the decline in the local population.¹⁵ Diagnosis is made by detection of HBV surface antigen (HBsAg) in serum. Viral replication varies between patients and those with active viral replication should be treated with nucleoside analogues such as tenofovir or entecavir to suppress viral replication and thereby reduce disease progression and the risk of hepatocellular carcinoma.¹⁶

Other causes

Liver cirrhosis due to autoimmune hepatitis is an increasingly common but under-diagnosed cause. It develops after successive bouts of liver inflammation and is diagnosed by blood tests (identification of autoantibodies) and histological findings; treatment consists of glucocorticoids and azathioprine.¹⁷ Primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) should be considered in patients with analytical abnormalities mainly in the form of cholestasis (increased gamma-glutamyl transferase [GGT] and alkaline phosphatase [ALP]), and haemochromatosis and Wilson's disease also require specialised attention for diagnosis and treatment.¹

Physiopathology

Liver cirrhosis is defined as the replacement of healthy liver tissue with scar tissue, mainly collagen, leading to the formation of regeneration nodules.¹ Liver fibrosis is a dynamic process resulting from chronic inflammation of liver tissue, caused by the various aetiological factors described above (viruses, alcohol, steatosis, etc.). This inflammation promotes collagen production and the accumulation of extracellular matrix, leading to the formation of scar tissue that eventually forms regeneration nodules, which histologically defines cirrhosis. These structural abnormalities cause a distortion in the vascular architecture of the liver that increases resistance to portal blood flow and triggers the progressive onset of portal hypertension. The progressive increase in portal pressure is responsible for most of the clinical complications of the disease.¹⁸

Natural history and complications

Physical examination findings suggestive of cirrhosis are mainly seen in patients with decompensated disease, although they can also be identified in those with compensated cirrhosis.¹ Spider angiomas on the upper part of the trunk and face are characteristic, while palmar erythema may be seen on the hands. Another finding suggestive of chronic liver disease is the loss of secondary sexual characteristics, mainly hair loss, and the development of gynaecomastia. Abdominal examination may reveal an enlarged and irregular left hepatic lobe and splenomegaly, and occasionally distension of the abdominal veins may be observed.¹

Chronic liver disease progresses silently over years, in an asymptomatic state called compensated cirrhosis; when complications associated with the disease develop, we speak of decompensated cirrhosis.¹ The most important complications are discussed below:

Ascites

Ascites is defined as the accumulation of fluid in the peritoneal cavity.¹⁹ For patients with cirrhosis, ascites usually has a protein concentration below 30 g/L and manifests as an increase in abdominal circumference causing patient discomfort, and is often accompanied by lower limb oedema.^19,20

It is the most common complication in patients with cirrhosis²¹ and is associated with an increased risk of other complications of the disease.²¹ Its occurrence carries a poor prognosis as well as a significant deterioration in the quality of life of patients. The five-year survival probability for patients with cirrhosis and ascites is approximately 30%, compared to 80% survival for patients with compensated cirrhosis.^21,22

Ascites is classified according to either volume or response to low sodium diet and diuretic treatment (Table 2).²⁰ For its treatment it is important to assess urinary sodium excretion, as this parameter is related to the response to diuretic treatment, as well as to the prognosis of patients: the lower the sodium excretion at baseline, the worse the prognosis of patients and the more difficult the response to diuretics. Treatment of ascites consists of a low-sodium diet (approximately 80 mEq sodium per day) combined with diuretic treatment, with spironolactone being the treatment of choice, associated or not with furosemide.²⁰

Table 2.

Classification of ascites.

Criterion	Ranking	Definition	Treatment
Depending on the volume of the ascites	Grade 1	Ascites detectable only by abdominal ultrasound.	Low sodium diet ± diuretic agent
	Grade 2	Moderate ascites, detectable by physical examination.	Low-sodium diet + diuretic agent
	Grade 3	Abundant ascites, resulting in significant abdominal distention.	Low sodium diet + diuretic agentTherapeutic paracentesis as a first option.Consider TIPS in selected patients.
Depending on the response to diuretics	Respondent	Ascites that can be controlled by diuretic treatment without developing associated complications.	Low-sodium diet + diuretic
	Recurrent	Ascites that recurs despite adequate treatment at least three times within a one-year period, ranging from grade 2 and/or grade 3.	Low-sodium diet + diuretic
	Refractory	Ascites that cannot be eliminated or whose early recurrence cannot be prevented by diuretic treatment because of lack of response to maximal diuretic treatment (refractory) or development of diuretic-related complications that prevent the use of an effective dose of diuretics (intractable).	Therapeutic paracentesis as a first option.Consider TIPS in selected patients.

TIPS: transjugular intrahepatic portosystemic shunt.

Gastrointestinal bleeding due to portal hypertension

Gastrointestinal bleeding from ruptured oesophagogastric varices is the second most common complication in patients with cirrhosis and is associated with a six-week mortality of 20%.²⁰ The risk of variceal bleeding is mainly related to the size of the varices and increases with the severity of liver dysfunction. Primary prophylaxis in patients with high-risk varicose veins and/or poor liver function should consist of treatment with non-cardioselective beta-blockers or regular endoscopic ligation of varicose veins. In patients with a history of variceal bleeding, secondary prophylaxis should be established with a combination of both strategies.² Patients may also present with bleeding associated with gastropathy, enteropathy or portal hypertension colopathy, which tends to be more insidious than varicose veins and usually manifests as anaemia.

Hepatic encephalopathy

HE is defined as the spectrum of potentially reversible neuropsychiatric abnormalities secondary to liver dysfunction and/or the presence of portosystemic shunts, and ranges from minimal encephalopathy (grades 0 and 1) to clinically overt encephalopathy (grades 2, 3 and 4).²³ Overt clinical manifestations of HE develop in 30–45% of patients with cirrhosis,²³ and it is the most common complication causing hospital admission and readmission.²⁴ All this has a significant impact on the quality of life of patients and their carers.²⁵

Acute renal failure and hepatorenal syndrome

Acute renal failure (ARF) is a common complication in patients with liver cirrhosis, with an estimated prevalence of 20–50% in patients admitted for decompensation of cirrhosis.²⁶ The development of ARF leads to high mortality in both the short and long term (28% at 30 days and 63% at one year). The presence of ARF is determined by the increase in creatinine from baseline and the diagnostic criteria and classification are summarised in Table 3.²⁷

Table 3.

Diagnostic criteria and classification of acute renal failure and hepatorenal syndrome in patients with cirrhosis of the liver.

Definition of ARF in patients with liver cirrhosis
Increase in SCr of at least 0.3 mg/dL (>26.5 μmol/L) in 48 h, or a 50% increase in SCr from baseline, presumably occurring within the last 7 days.
ARF stage 1A	SCr increase ≥0.3 mg/dL (≥26.5 μmol/L) or ≥50% of baseline SCr value over 48 h, with a final value of SCr <1.5 mg/dL (133 μmol/L).
ARF stage 1B	SCr increase ≥0.3 mg/dL (≥26.5 μmol/L) or ≥50% of baseline SCr value over 48 h, with a final SCr value ≥1.5 mg/dL (133 μmol/L).
ARF stage 2	SCr increase of 2–3 times the baseline SCr value
ARF stage 3	Increase in SCr greater than 3 times the baseline SCr value, SCr ≥ 4.0 mg/dL (353.6 μmol/L) with an increase of at least 0.3 mg/dL (26.5 μmol/L), or need for initiation of renal replacement therapy.
Diagnostic criteria for HRS-ARF according to the International Club of Ascites
Cirrhosis with ascites
Diagnosis of ARF according to the definition above.
No improvement after 48 h of withdrawal of diuretic treatment and expansion with albumin (1 g/kg body weight).
Absence of shock.
No concomitant or recent use of nephrotoxic drugs (NSAIDs, aminoglycosides, iodinated contrast agents, etc.).
Absence of markers of structural renal injury, defined as:Absence of proteinuria (<500 mg/d)Absence of microhaematuria (<50 red blood cells per field)Absence of pathological findings on renal ultrasonography

NSAIDs: non-steroidal anti-inflammatory drugs; SCr: serum creatinine; ARF: acute renal failure.

Patients with cirrhosis can develop ARF for a variety of reasons. Identifying the cause is a fundamental aspect in determining treatment and prognosis. The most common causes of ARF in patients with cirrhosis are those associated with hypovolemia (related to excessive diuretic therapy, excessive gastrointestinal losses or associated with gastrointestinal bleeding) and acute tubular necrosis (ATN).

Patients with cirrhosis of the liver can develop a specific type of ARF: hepatorenal syndrome (HRS-ARF).²⁸ HRS-ARF is a specific form of ARF in patients with decompensated cirrhosis characterised by a significant reduction in renal blood flow leading to a severe reduction in glomerular filtration rate. There is a subtype of HRS with a more insidious presentation in which patients have a reduced glomerular filtration rate for more than three months without meeting the criteria for ARF. These patients are classified as hepatorenal syndrome-chronic kidney disease (HRS-CKD). HRS-ARF and HRS-CKD have replaced the former nomenclature of HRS type 1 and type 2, respectively.^27,28 The diagnosis of HRS-ARF is made only after ruling out other causes of ARF and confirming the absence of markers of structural acute kidney injury, such as haematuria, proteinuria or renal abnormalities on ultrasound (Table 3).

Bacterial infections

About 25% of hospitalised patients with cirrhosis have an infection during admission, with urinary tract infection and spontaneous bacterial peritonitis (SBP) being the most common types of infection in patients with cirrhosis.²⁹ Bacterial infections are usually associated with the development of other complications, such as HE or gastrointestinal bleeding, and may also lead to failure of organs other than the liver, resulting in acute-on-chronic liver failure syndrome (ACLF).^30,31 It is important to note that patients with cirrhosis who have bacterial infections may not present with the typical features of infection in patients without liver disease. Therefore, bacterial infections should be ruled out in all patients presenting with complications of cirrhosis or acute decompensation of liver or kidney function.

SBP is defined as bacterial infection of ascitic fluid, with no identifiable intra-abdominal source of infection.²⁰ The clinical presentation of SBP is very heterogeneous and may be asymptomatic and therefore diagnostic paracentesis should be performed in all decompensated patients hospitalised with cirrhosis and presenting with ascites, regardless of the presence or absence of symptoms or signs of infection.²⁰ Although early diagnosis and appropriate treatment have improved the prognosis of SBP over the years, in-hospital mortality remains high at approximately 20%.

Acute-on-chronic liver failure

ACLF occurs in approximately 30% of patients hospitalised for cirrhosis and carries a poor prognosis.³² ACLF is a syndrome characterised by acute decompensation of cirrhosis associated with a rapid deterioration of the patient's clinical condition due to the development of multi-organ failure. A precipitating factor can be identified in most patients with ACLF. Bacterial infections and alcohol consumption are the most common precipitating factors in patients with ACLF in Europe and the USA, while viral hepatitis is the most common precipitating factor in patients in Asia.³⁰ It is important to note that in some patients, no precipitating factor can be identified.

Recompensation

Some patients with decompensated cirrhosis may experience clinical improvement, usually progressive and slow, by treating the underlying causes responsible for the cirrhosis and progressing to a state similar to compensated cirrhosis; this process is known as recompensation.² This is associated with an improvement in the prognosis of these patients, with a significant reduction in long-term mortality, and may avoid the need for liver transplantation in some patients.¹⁰

Diagnosis

The diagnosis of liver cirrhosis is established either on the basis of histological features or on the combination of clinical, analytical and imaging parameters.¹

The diagnosis of patients with compensated cirrhosis is usually made on an incidental basis, following the assessment of patients with laboratory abnormalities, mainly liver parameters, as well as thrombocytopenia, or based on the evaluation of patients with risk factors for chronic liver disease (obesity, type 2 diabetes, excessive alcohol consumption, etc.). In patients with suspected compensated cirrhosis, the aim is to assess the degree of liver fibrosis and the possible presence of portal hypertension and to determine the causes of the disease.¹ These factors are strongly associated with the risk of progression and the development of complications of cirrhosis and inform the type of follow-up needed. Although liver biopsy is the gold standard for determining the degree of fibrosis, its use is limited to selected cases, particularly where there is doubt about the aetiology of the disease. For this reason, several non-invasive tests (NITs) have been developed which, with simple laboratory parameters and some demographic and clinical data, allow an estimation of liver fibrosis.³³ These tests allow the identification of subjects with liver fibrosis and/or cirrhosis. Examples are the Liver Risk Score, the Fibrosis-4 index (FIB-4) or the AST-to-platelet ratio index (APRI), among others (Table 4).^1,34–36

Table 4.

Non-invasive tests for the diagnosis of advanced fibrosis.

Non-invasive test	Variables assessed	Cut-off points	Sensitivity and Specificity
APRI	AST, platelets	≥1.00	Se = 0.56 (0.21−0.77)Sp = 0.84 (0.56–1.00)
FIB-4	AST, ALT, platelets and age	Discard: <1.3Diagnosis: ≥ 2,676	Se = 0.80 (0.76−0.83)Sp = 0.79 (0.77−0.81)
NFS	AST, ALT, platelets, albumin, age, BMI, and diabetes	Discard: <−1,455Diagnosis: >0.676	Se = 0.77 (0.69−0.84)Sp = 0.70 (0.67−0.73)
LRS	AST, ALT, GGT, platelets, cholesterol, glucose, age and gender	≥10	Se = 0.96 (0.95−0.96)Sp = 0.59 (0.51−0.67)
ELF	HA, TIMP-1, PIIINP.	≥9.8	Se = 0.65 (0.49−0.77)Sp = 0.86 (0.77−0.92)
Hepascore	α 2M, HA, bilirubin and GGT, age and sex	0.52−0.97	Se = 0.80 (0.73−0.75)Sp = 0.87 (0.83−0.89)
FibroTest	GGT, bilirubin, α2M, ApoA1, haptoglobin, age and sex	0.57−0.75	Se = 0.63 (0.35−0.84)Sp = 0.92 (0.89−0.94)
Transient Elastography (TE)	Liver stiffness	≥10 kPa	Se = 0.80 (0.77−0.83)Sp = 0.77 (0.74−0.80)

ApoA1: apolipoprotein A1; APRI: AST-to-platelet ratio index; AST: aspartate aminotransferase; ALT: alanine aminotransferase; α2M: alpha-2-macroglobulin; BMI: body mass index; Sp: specificity; ELF: enhanced liver fibrosis test; FIB-4: fibrosis-4 index; GGT: gamma-glutamyl transferase; HA: hyaluronic acid; LRS: liver risk score; NFS: NAFLD fibrosis score; PIIINP: procollagen III N-terminal propeptide; Se: sensitivity; TE: transient elastography; TIMP-1: tissue inhibitor of metalloproteinases-1.

Adapted from Ref.⁵⁴

In addition to NITs, other more direct methods, such as liver elastography, can be used to assess the degree of liver fibrosis. Transient elastography (TE) is a radiological technique that measures liver stiffness and correlates well with the degree of fibrosis (Fig. 1).³⁷ TE has been validated for the evaluation of various aetiologies of liver disease and is the test of choice for its ease of use and usefulness in assessing the presence of fibrosis.³⁵ The "rule of 5" has been proposed to determine the presence or absence of advanced fibrosis, cirrhosis and portal hypertension.² Generally speaking, in patients with a TE <10 kPa advanced fibrosis can be ruled out, patients with TE between 10 and 15 kPa have advanced fibrosis, while patients with TE >15 kPa have a high likelihood of liver cirrhosis. Finally, a TE >20 kPa is usually indicative of cirrhosis with clinically significant portal hypertension.^1,33,35

Figure 1.

Estimation of the degree of liver fibrosis by transient elastography and "rule of 5" for the risk of liver cirrhosis.

Note: The "rule of 5" should be treated with caution as it has not been clearly demonstrated, particularly in general population studies.

Adapted from Refs.^1,2,37

The diagnosis of decompensated cirrhosis is less complex. It is based on a combination of physical examination findings, the presence of characteristic complications (ascites, encephalopathy, variceal bleeding), typical analytical abnormalities (thrombocytopenia, decreased prothrombin time, hypergammaglobulinemia), ultrasound findings compatible with the diagnosis of cirrhosis (irregular liver border, signs of portal hypertension) and/or the presence of oesophagogastric varices on fibrogastroscopy1. In cases where this combination of factors is present, liver biopsy is not necessary.

Treatment and prognosis

The treatment of cirrhosis of the liver is based on the treatment of the aetiological factor of the liver disease on the one hand, and on the treatment and prevention of the complications of the disease on the other.²⁰

Aetiological treatment

Treatment specific to the cause of cirrhosis is essential and includes alcohol abstinence for cirrhosis associated with excessive alcohol consumption, antiviral treatment for viral hepatitis or control of metabolic risk factors in metabolic fatty liver cirrhosis. Several studies have shown that treatment of the cause of cirrhosis is able not only to slow the progression of cirrhosis, but in many cases to reverse the onset of clinical decompensation in the decompensated cirrhosis phase.²⁰

Treatment of complications

With regard to the clinical complications of cirrhosis, the treatment of these complications currently consists of administering specific therapies for each of them, e.g. diuretic treatment for ascitic oedematous decompensation, laxative treatment with disaccharides with or without a non-absorbable antibiotic (rifaximin) for HE²³ or treatment of gastrointestinal bleeding due to oesophageal varices with elastic bands placed endoscopically.² On the other hand, there are treatments aimed at preventing the development of specific complications of cirrhosis, such as the administration of non-absorbable antibiotics (norfloxacin) to prevent SBP in high-risk patients or non-selective beta-blockers to prevent gastrointestinal bleeding due to oesophageal varices.²⁰ The treatment of complications of liver cirrhosis is summarised in Table 5.

Table 5.

Treating the complications of cirrhosis.

Complications	Treatment	Prevention
Ascites	Combination of low sodium diet (<80 mEq/d) and diuretic treatment (combination of spironolactone with furosemide at increasing doses).^20In some cases, therapeutic paracentesis may be necessary. It is recommended to administer 8 g of albumin per litre of ascites removed.^20Individual assessment of the placement of TIPS.There are conflicting data on chronic outpatient albumin administration in patients with cirrhosis and ascites.^38,39For more information on the treatment of ascites (Table 2).
Gastrointestinal bleeding due to oesophagogastric varices	Haemodynamic stabilisation. Transfusion of blood products if Hb <7 g/dL in the absence of comorbidity (chronic kidney disease or ischaemic heart disease).^55Infusion of haemostatic therapy is recommended, mainly terlipressin or somatostatin.^2,20Antibiotic prophylaxis with Ceftriaxone 1 g/24 h (Child-Pugh B-C) or Norfloxacin 400 mg/12 h (Child-Pugh A).^56Endoscopic treatment by ligation. If there is no control, consider fitting an oesophageal prosthesis.Consider placement of TIPS in Child-Pugh B or C <13 points within 72 h after control of bleeding, or in case of haemostasis failure or recurrence of bleeding.^2,20,57	Primary prophylaxis with beta-blockers or endoscopic ligation every 3 weeks until eradication in patients with large varicose veins and/or high-risk stigmata (red dots), or small varicose veins in Child-Pugh C patients.Secondary prophylaxis with beta-blockers and endoscopic ligation every 3 weeks until eradication in all patients with a previous episode of variceal bleeding.
Hepatic encephalopathy	Active search for triggers (infections, drugs, bleeding, dehydration) and targeted treatment.^23Non-absorbable disaccharides (lactulose) orally and/or enema according to HE grade.Ensure airway protection in comatose patients.	Non-absorbable oral disaccharides after the first episode.Rifaximin 400 mg/8 h or 600 mg/12 h indefinitely in case of recurrence despite disaccharide treatment.^23
Spontaneous bacterial peritonitis	Intravenous antibiotic therapy considering the local epidemiology of multi-resistant germ infections.^20Administration of albumin on days 1 and 3 of the diagnosis of SBP at 1.5 g/kg and 1 g/kg (maximum 100 g), respectively.^20Ascitic fluid monitoring by diagnostic paracentesis every 48 h is recommended. A favourable outcome is considered in cases where there is a 25% decrease in the total PMN count in the ascitic fluid.	Primary prophylaxis, in those patients with low ascitic fluid protein count (<15 g/L) and poor liver function (bilirubin >3 mg/dL) or renal dysfunction (SCr > 1,2 mg/dL or Na <130 mEq/L). The use of car 400 mg/24 h^20 is recommended.Secondary prophylaxis, in all patients with a history of SBP. The recommended regimen is the same as for primary prophylaxis.Ciprofloxacin or co-trimoxazole may be used in cases where norfloxacin is not available.
Acute renal failure	Identification and treatment of potential triggers (infections, drugs, gastrointestinal losses).If ARF > 1B, administration of albumin (1 g/kg) for 48 h.^28 If HRS-ARF criteria are met, consider transplantation and start treatment with terlipressin (preferably continuous infusion pump) and albumin (40 g/d).^28,58,59	The administration of albumin has been shown to decrease the risk of ARF in patients with SBP and therapeutic post-paracentesis.^60

ARF: acute renal failure; HRS-ARF: hepatorenal syndrome - acute renal failure; HE: hepatic encephalopathy; SBP: spontaneous bacterial peritonitis; PMN: polymorphonuclear; SCr: serum creatinine; TIPS: transjugular intrahepatic portosystemic shunt.

Prevention of disease progression

In recent years, research has been conducted on the efficacy of different treatments to prevent the progression of cirrhosis and its complications in order to improve the prognosis of the disease.

Contradictory results have been reported regarding the effect of chronic albumin administration in patients with decompensated liver cirrhosis with ascites, and further studies on the effect of this treatment in decompensated cirrhosis are required before recommending its use in clinical practice.^38,39

A recently published study also evaluated the use of beta-blockers in patients with compensated cirrhosis against a combined endpoint of complications of cirrhosis or liver-related death.⁴⁰ The result was positive for the combined primary endpoint, but it remains to be shown whether this treatment has a beneficial effect on cirrhosis-related mortality.

Finally, a recent study in patients with decompensated cirrhosis has evaluated the effect of combination therapy with simvastatin and rifaximin, for which there were previous data on their potential beneficial effects in liver cirrhosis. The results of this study showed no benefit of this treatment combination on the occurrence of complications of cirrhosis or on survival.⁴¹

As there are currently no effective treatments proven to improve survival in patients with decompensated cirrhosis, liver transplantation is the only proven effective alternative. Therefore, all patients with decompensated cirrhosis and a Model for End-stage Liver Disease (MELD) score (see below) of 15 or more should be considered for liver transplantation.⁴²

Prognosis

The prognosis for patients with cirrhosis depends on the clinical stage of the disease, with median survival for patients with compensated cirrhosis being approximately 10 years from diagnosis and for patients with decompensated cirrhosis being approximately two years.^21,22

There are two classifications currently used to assess the prognosis of patients with cirrhosis. One of these is the Child-Turcotte-Pugh classification, which uses serum albumin, bilirubin levels, prothrombin time and presence of ascites and encephalopathy.⁴³ The other is MELD, which uses three laboratory variables, bilirubin, creatinine and the International Normalized Ratio (INR), and produces a numerical score from six to 40 points with increasing severity.⁴⁴ Several subsequent modifications of this classification have been published, the most widely used being MELD-sodium, which includes plasma sodium levels and has been shown to improve the prognostic ability of MELD and is now widely used in different parts of the world to prioritise patients with cirrhosis on the liver transplant list.⁴⁵

In addition to the stage of the disease (compensated/decompensated), survival in patients with cirrhosis is also influenced by the presence of comorbidities and the patient's age.^46–49 Comorbidities are particularly important in cirrhosis caused by MASLD (ischaemic heart disease, chronic kidney disease, arterial vascular disease, etc.).

Future perspectives

Liver cirrhosis represents a serious health problem with a great impact on our environment, especially on the working population. Despite the dramatic reduction of hepatitis C as a cause of cirrhosis, thanks to the development of DAAs, cirrhosis-related mortality worldwide has not decreased in recent years. Some studies indicate that the number of affected patients will increase progressively in the coming years.^6,50 This increase is expected to be associated with an increase in the number of patients with metabolic liver disease, in parallel with a rise in the prevalence of cardiovascular risk factors such as obesity, diabetes mellitus 2 (DM2) or hypertension, similar to that experienced in the US in the 2000s.⁵¹ In the absence of effective treatment for patients with advanced liver disease, a strategy for the early identification of patients with liver fibrosis has now been proposed to identify those patients at risk of developing liver complications and to implement therapeutic measures aimed at controlling the factors that promote disease progression and, ultimately, decompensation and death. Several international projects are currently underway to evaluate potential screening strategies for liver fibrosis in the general population and in specific at-risk populations.^52–54 The results of this research should help to identify the best strategy for early diagnosis in the population and assess whether it is cost-effective at a population level.

Ethical considerations

In this literature review, we confirm that all ethical standards required by Elsevier for publication in peer-reviewed journals have been met. We ensure the originality of the content, with proper acknowledgement of sources and no plagiarism. There are no conflicts of interest and all authors have made a substantial contribution to the work, in accordance with authorship standards. We have carefully reviewed the literature and adhered to established ethical principles of publication.

Funding

This work has been funded by the Horizon 2020 framework programme of the European Commission, under the call SC1-BHC-30-2019 through grant No. 847989. The funder was not involved in the study design, data collection, analysis and interpretation, nor in the writing of this manuscript. This article has received support from grants (number PI20/00579, PI22/00910) included in the Plan Nacional I+D+i and co-funded by the Instituto de Salud Carlos III-Proyectos de Investigación en Salud-Acción Estratégica en Salud (AES), 2020 and 2022, respectively, of which Dr Ginès and Dr Pose are beneficiaries.