Cirrhosis develops progressively as a result of damage to the liver (which can be due to a number of causes), usually over a number of years. The normal smooth liver structure becomes distorted, with nodules surrounded by fibrosis. This affects the liver's synthetic, metabolic and excretory actions.

Cirrhosis can be described as:

• Compensated — when the liver can still function effectively and there are no, or few, noticeable clinical symptoms.
• Decompensated — when the liver is damaged to the point that it cannot function adequately and overt clinical complications (such as jaundice, ascites, variceal haemorrhage, and hepatic encephalopathy).

Risk factors

• The most common risk factors for cirrhosis in the UK and Europe include:
  • Alcohol misuse
  • Hepatitis B and C infection
  • Obesity (body mass index of 30 kg/m² or more) or type 2 diabetes — people in these groups are at risk of cirrhosis if they have non-alcoholic fatty liver disease (NAFLD)
• Less common causes of cirrhosis include:
  • Autoimmune liver disease (for example, autoimmune hepatitis, primary biliary cholangitis, primary sclerosing cholangitis)
  • Genetic conditions (for example, haemochromatosis, Wilson's disease, alpha-1 antitrypsin deficiency, cystic fibrosis)
  • Medication use, usually over a long period of time (for example, methotrexate)
  • Budd-Chiari syndrome (hepatic vein outflow obstruction)
  • Sarcoidosis and glycogen storage disease

Complications

Portal hypertension (a pathological increase in portal venous pressure) is one of the earliest sequelae of cirrhosis, and many complications of cirrhosis arise as a result of this rather than hepatocyte failure.

• The major complications of cirrhosis are:
  • Ascites
    • Ascites is a pathological fluid accumulation in the peritoneal cavity as a result of splanchnic vasodilation and sodium and water retention. It causes abdominal swelling, bloating, and pain, and is the most common complication of cirrhosis often necessitating hospital admission. Newly diagnosed ascites always requires urgent evaluation with imaging, usually starting with an abdominal ultrasound scan to confirm or refute the diagnosis and detect evidence of cirrhosis or malignancy. Doppler ultrasound and diagnostic paracentesis are also required. People with cirrhosis and ascites are at high risk of further complications such as spontaneous bacterial peritonitis, hyponatraemia, and hepatorenal syndrome.
    • N.B. Other causes of portal hypertension that may be associated with ascites include congestive heart failure, constrictive pericarditis, alcoholic liver disease, fulminant hepatitis, subacute hepatitis, massive liver metastasis, and Budd-Chiari syndrome. Conditions causing hypoalbuminaemia such as nephrotic syndrome and protein-losing enteropathy may result in ascites. Peritoneal diseases including infectious peritonitis and malignancies can also cause ascites.
  • Hepatic encephalopathy
    • Hepatic encephalopathy is a dysfunction of the brain as a result of liver insufficiency and/or portosystemic shunting and is related to the effect of nitrogenous waste products (such as ammonia and glutamine) on the brain. It presents with a variety of symptoms, including cognitive and behavioural changes (for example irritability, disinhibition, disorientation), personality changes, sleep disturbance, motor problems, and altered level of consciousness. Symptoms vary in severity, with mild hepatic encephalopathy only detectable using psychometric or neurophysiological testing and severe cases experiencing acute confusion, agitation, and coma. Hepatic encephalopathy is usually associated with a predisposing event, for example, constipation, dehydration, infection, gastrointestinal bleeding, or drugs (for example opiates, benzodiazepines, diuretics). Serum ammonia levels are usually elevated, but there is poor correlation between ammonia level and the degree of encephalopathy.
  • Haemorrhage from oesophageal varices
    • The increase in portal pressure causes varices as a result of dilation of veins in the oesophagus and stomach. Rupture of varices and associated bleeding, which can present as haematemesis or melaena, has a high mortality rate. Risk factors for rupture include size of varices, severity of liver disease, sepsis, and hepatocellular carcinoma.
  • Infection
    • People with cirrhosis are at increased risk of bacterial infection and sepsis because of immune dysfunction resulting from cirrhosis. The most commonly occurring infections in this group are spontaneous bacterial peritonitis (when the body's natural bacteria cause infection of ascitic fluid), urinary tract infection, pneumonia, cellulitis, and bacteraemia. Bacterial infections have a significant role in progression of liver failure, development of complications, and mortality in people with cirrhosis. The body's response to infection increases the risk of serious complications such as shock and renal failure because of the haemodynamic dysfunction that is already present in cirrhosis. Risk factors for infection in people with cirrhosis include reduced liver function, low protein ascites, and variceal bleeding.
• Other complications include:
  • Hepatorenal syndrome — results from changes to the circulation due to the effects of cirrhosis, plus sodium and water retention and renal vasoconstriction. The resulting decrease in renal blood flow leads to a reduced glomerular filtration rate and hepatorenal syndrome.
  • Hepatopulmonary syndrome - results from portal hypertension and symptoms include dyspnoea and platypnoea.
  • Hepatocellular carcinoma.
  • Portal hypertensive gastropathy.
  • Portal vein thrombosis.
  • Cardiovascular complications including circulatory changes (such as decreased blood pressure), and cirrhotic cardiomyopathy.

Clinical features

Suspect cirrhosis:

• In high risk groups (e.g. alcohol misuse, intravenous drug use, high risk sexual activity, obesity), especially if there are non-specific symptoms such as malaise, fatigue, anorexia, nausea, weight loss, muscle wasting, or abdominal pain.
• If examination identifies:
  • Palpable left lobe of the liver, hepatomegaly, splenomegaly.
  • The presence of stigmata of chronic liver disease
    • Spider naevi
    • Palmar erythema
    • Leuconychia
    • Muscle wasting
    • Finger clubbing
    • Dupuytren's contracture
    • Xanthelasma
    • Gynaecomastia
    • Caput medusae
    • Hepatosplenomegaly
  • Features of severe liver impairment and signs of decompensated liver disease, such as:
    • Jaundice (examine the sclera under natural light)
    • Abnormal bruising
    • Peripheral oedema
    • Ascites - abdominal distension, shifting dullness
    • Sepsis
    • Variceal bleeding
    • Encephalopathy (Characterised by changes in consciousness, behaviour, and personality with disorientation, drowsiness, forgetfulness, confusion, agitation, and eventual coma. Slurred speech, asterixis (liver flap), increased muscle tone, and extensor plantar reflexes may be present.)
• If a person is known to have chronic liver disease and has a low platelet count, elevated aspartate aminotransferase (AST): alanine transaminase (ALT) ratio, high bilirubin, low albumin, or increased prothrombin time or international normalised ratio (INR).

Investigations

• All patients should receive a liver screen on presentation in order to identify the underlying cause and severity of the cirrhosis:
  • LFTs
    • Aminotransferases (aspartate aminotransferase [AST], alanine aminotransferase [ALT]) levels increase with hepatocellular damage and are usually elevated to some degree. An AST/ALT ratio of ≥1 is thought to be a predictor of cirrhosis.
    • Increases in GGT represents enzyme activation, which can be induced by alcohol and certain drugs. GGT is not significantly present in bone, such that concomitant elevated GGT and alkaline phosphatase (ALP) indicates the liver as the source of the ALP. Cholestasis causes an increase in alkaline phosphatase and gamma-glutamyl transferase (GGT) with minimal derangement of AST and ALT.
    • Total bilirubin may be normal in patients with compensated cirrhosis, but as the cirrhosis progresses, serum levels generally rise.
    • A decrease in the serum albumin is a marker of hepatic synthetic dysfunction.
  • FBC – infection, anaemia, thrombocytopenia
  • U&Es – renal impairment, hyponatraemia
  • Clotting – prolonged prothrombin time
  • Viral serology - hepatitis A, B and C
  • Autoantibody profile - ANA and SMA for autoimmune hepatitis, AMA for PBC
  • Ferritin and transferrin saturation – hereditary haemochromatosis
  • Alpha1-antitrypsin - alpha1-antitrypsin deficiency
  • Alpha-fetoprotein – hepatocellular carcinoma
  • Caeruloplasmin – Wilson’s disease
• Signs of advanced cirrhosis may be detected using ultrasound, computed tomography (CT) scan, and magnetic resonance imaging (MRI). Transient elastography is an ultrasound-based technique for detecting hepatic fibrosis and cirrhosis without the need for liver biopsy. As with non-invasive blood tests for fibrosis evaluation, transient elastography has best diagnostic performance in excluding liver cirrhosis.
• Liver biopsy remains the most specific and sensitive test for the diagnosis of cirrhosis. However, it is not necessary in patients with advanced liver disease and typical clinical, laboratory, and/or radiological findings of cirrhosis, unless there is a need to determine the degree of inflammation.
• Patients with cirrhosis should be offered upper gastrointestinal endoscopy for screening of gastro-oesophageal varices at the time of diagnosis, and at 1-3-year intervals thereafter.
• Every patient with new-onset ascites should undergo a diagnostic paracentesis: cell count with differential, albumin, and total protein should be measured in the ascitic fluid. Ascitic fluid should also be sent for cytology. The serum-ascites albumin gradient (SAAG) should be calculated: a SAAG of ≥1.1 g/dL with low ascitic fluid total protein is consistent with portal hypertension secondary to cirrhosis.
• Patients with cirrhosis, especially those with viral hepatitis (type B and C), alcohol-related liver disease, and haemochromatosis, are at high risk of developing hepatocellular carcinoma and should therefore undergo surveillance with ultrasound, with or without alpha-fetoprotein, every 6 months.

Management

• Ascites
  • Evidence suggests that severe dietary sodium restriction may be more harmful than beneficial, and many clinicians advise a no-added-salt diet rather than a low-salt diet.
  • First-line choice of diuretic should be spironolactone due to its effects on aldosterone. Furosemide may be added in patients who do not respond. Renal function and electrolytes should be monitored carefully when initiating diuretics and after dose escalation. NSAIDs, ACE inhibitors, and other nephrotoxins should be avoided in patients with ascites.
  • Some patients may develop large volume ascites refractory to medical treatment because of lack of efficacy, or unacceptable adverse effects or complications. These patients may require recurrent large-volume paracentesis (LVP) and albumin replacement for symptom control.
  • Patients not suitable for liver transplantation should be considered for transjugular intrahepatic portosystemic shunt (TIPSS) placement. Although TIPSS has been shown to be more effective than LVP and albumin, it is associated with a higher incidence of hepatic encephalopathy and shows no survival benefit.
  • The prognosis of patients with refractory ascites is poor. If TIPSS/transplantation are not viable options, then long-term drain placement for intermittent small-volume paracentesis may be considered as a palliative measure.
  • The use of vaptans (vasopressin V2-receptor antagonists) may have a slight beneficial effect on ascites and hyponatraemia, but they do not reduce mortality, liver complications, or renal failure.
• Spontaneous bacterial peritonitis
  • Spontaneous bacterial peritonitis is an infection of previously sterile ascitic fluid without apparent intra-abdominal source of infection. Abdominal pain and fever are the most characteristic symptoms. Diagnostic paracentesis is the most important test to confirm ascites and help diagnose the cause and to determine if the fluid is infectious.
  • A peritoneal fluid absolute neutrophil count >250 cells/mm³ is the accepted criterion for the diagnosis for spontaneous bacterial peritonitis. Treatment is with intravenous cefotaxime or a fluoroquinolone and intravenous human albumin solution.
  • All patients who have survived an episode of spontaneous bacterial peritonitis require lifelong secondary antibiotic prophylaxis.
  • Patients with ascites and an ascitic fluid total protein level of ≤1 g/dL are at high risk of developing spontaneous bacterial peritonitis, and should be considered for primary antibiotic prophylaxis.
• Gastroesophageal varices
  • Prophylaxis with either non-selective beta-blockers (propranolol, nadolol, or carvedilol) or endoscopic variceal ligation (EVL), which requires several sessions to obliterate varices, should be implemented if gastro-oesophageal varices are present.
  • An episode of acute variceal haemorrhage should be managed as a medical emergency with intravascular volume support, blood transfusion (with the aim of keeping the haemoglobin around 70-80 g/L) and a combination of endoscopic and pharmacological therapy.
  • Terlipressin (a vasopressin analogue) should be initiated as soon as a variceal bleed is suspected and continued for 3-5 days if it is confirmed.
  • Upper gastrointestinal endoscopy should be performed within 12 hours to confirm the diagnosis and allow treatment with EVL or sclerotherapy. Transjugular intrahepatic portosystemic shunting (TIPSS) may be used to treat patients at high risk of failed endoscopic variceal ligation or re-bleeding.
  • Short-term (up to 7 days) antibiotic prophylaxis with norfloxacin should be instituted in all patients following a gastrointestinal haemorrhage (regardless of the presence of ascites) as this has been shown to decrease the rate of bacterial infections and increase survival.
  • Life-threatening bleeding may be controlled with a Sengstaken-Blakemore tube or a Danis stent until haemostasis can be achieved endoscopically, or with TIPSS with or without embolisation.
• Hepatic encephalopathy
  • Precipitating factors include gastrointestinal haemorrhage, constipation, diarrhoea and vomiting, hypoglycaemia, and electrolyte imbalance; drugs (diuretics, sedatives) and medical procedures (paracentesis, TIPSS); infection, anaemia, hypoxia, and hypotension.
  • Serum electrolytes, liver tests, urea and creatinine, full blood count, serum glucose, arterial or venous blood gas, coagulation profile, urine toxin screen, urine culture, and blood cultures should be ordered. A chest x-ray and head computed tomography (CT) scan may help to rule out other diagnoses. Lumbar puncture might be considered to exclude meningitis as a cause of altered mental status. An upper-quadrant ultrasound should be considered in all patients with unexplained acute decompensation, as acute portal or hepatic vein thrombosis can be the cause. In patients with ascites, a diagnostic paracentesis should also be performed to rule out spontaneous bacterial peritonitis, which may precipitate HE.
  • Treatment involves identification and correction of reversible precipitating factors and lactulose, used alone or in combination with antibiotics such as rifaximin. Appropriate candidates should be referred to liver transplant centres after a first episode of encephalopathy.
• Liver transplantation
  • Patients who develop complications of cirrhosis such as hepatocellular carcinoma or signs of decompensation (ascites, jaundice, variceal haemorrhage, portal systemic encephalopathy, hepatopulmonary syndrome or hepatorenal syndrome) should be referred for liver transplant evaluation without delay. Transplant assessment may be a prolonged process and early referrals are preferable. Orthotopic liver transplantation remains the only curative treatment option for patients with decompensated cirrhosis.