Cirrhosis

In cirrhosis, there is progressive and diffuse fibrosis (replacement of injured tissue by scarring) and the development of widespread nodules throughout the liver as a result of a chronic insult to the liver.

• The fibrosis causes distortion of the hepatic vasculature and it can lead to an increased intrahepatic resistance and portal hypertension.
• Portal hypertension can lead to oesophageal varices as well as hypoperfusion of the kidneys, water and salt retention and increased cardiac output.¹
• Hepatocyte damage causes impaired liver function. This means that the liver is less able to synthesise important substances such as clotting factors and is also less able to detoxify other substances.
• Coagulopathy, hepatic encephalopathy and eventually end-stage liver failure can result.
• Hepatocellular carcinoma may also develop as a complication of cirrhosis.
• Around 80 to 90% of the liver parenchyma needs to be destroyed before there are clinical signs of liver failure.²

• A number of chronic liver diseases can lead to cirrhosis.
• The cirrhotic process can take from weeks to many years to develop, depending on the underlying cause and other factors, including patient response to the disease process. For example, chronic hepatitis C infection can take up to 40 years to progress to cirrhosis in some people.³
• Common causes of cirrhosis include:
  • Alcohol abuse
  • Hepatitis B infection
  • Hepatitis C infection (up to 20% can develop cirrhosis)¹
  • Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) (up to 10% of patients with NASH can develop cirrhosis)^1,3
• Less common causes include:
  • Haemochromatosis
  • Primary biliary cirrhosis
  • Biliary obstruction (may be due to biliary atresia/neonatal hepatitis, congenital biliary cysts or cystic fibrosis)²
  • Autoimmune hepatitis
  • Inherited metabolic disorders, e.g. tyrosinaemia, Wilson's disease, porphyria, alpha-1-antitrypsin deficiency, glycogen storage diseases
  • Sarcoidosis or other granulomatous disease³
  • Primary sclerosing cholangitis
  • Venous outflow obstruction in Budd-Chiari syndrome or veno-occlusive disease³
  • Drugs and toxins including methotrexate, amiodarone and isoniazid^2,3
  • Congestive heart failure or tricuspid regurgitation (although this is rarely seen now due to improved management)³
  • Infections including congenital and tertiary syphilis and schistosomiasis²

• It is difficult to estimate the exact prevalence of cirrhosis as there is often undiagnosed disease and previously undiagnosed cirrhosis is often found at post mortem.
• There are an estimated 30,000 people living with cirrhosis in the UK and at least 7000 new cases being diagnosed each year. The numbers of people living with both alcoholic cirrhosis and non-alcohol-related cirrhosis seem to be rising.⁴
• There is concern that there are growing levels of dangerous alcohol consumption in the UK which may lead to increased numbers of people with cirrhosis.
• An analysis in the Lancet showed that between 1960 and 2002, total recorded alcohol consumption in Britain doubled.⁵
• The same report showed that between 1987-1991, and 1997-2001, cirrhosis mortality in men in Scotland more than doubled (104% increase) and in England and Wales rose by over two-thirds (69%). Mortality in women increased by almost half (46% in Scotland and 44% in England and Wales).⁵

Risk factors for cirrhosis

• Alcoholic liver disease and hepatitis C are the most common causes in developed countries.¹
• Hepatitis B is the most common cause in parts of Asia and in sub-Saharan Africa.¹
• There may also be a genetic predisposition to cirrhosis which may explain the variable rates of its development in people with similar risk factors (such as alcohol abuse or hepatitis C infection).¹
• Continued alcohol consumption increases the rate of progression of cirrhosis from any cause.
• Risk factors for the development of cirrhosis in those with chronic hepatitis C infection:^6,7
  • Regular (moderate) alcohol consumption
  • Age > 50 years
  • Being male
• Risk factors for the development of cirrhosis in those with non-alcoholic steatohepatitis:^1,8,9
  • Older age
  • Obesity
  • Insulin resistance or type 2 diabetes
  • Hypertension
  • Hyperlipidaemia

• Cirrhosis is often asymptomatic until there are obvious complications of liver disease. Up to 40% of people with cirrhosis may be asymptomatic.²
• Blood testing for other reasons may reveal abnormal liver function and prompt further investigation which shows cirrhosis.

Symptoms

Cirrhosis may present with vague symptoms such as:

• Fatigue
• Malaise
• Anorexia
• Nausea
• Weight loss

In advanced, decompensated liver disease, presentation may include:

• Oedema
• Ascites
• Easy bruising
• Poor concentration and memory
• Bleeding oesophageal varices
• Spontaneous bacterial peritonitis

Points in the history

• Take a full drug and alcohol history.
• Enquire about drugs that have been prescribed, bought over-the-counter or used recreationally. Ask about alternative remedies, especially herbal.
• Assess risk factors for hepatitis infection.
• Enquire about family history of autoimmune or liver diseases.

Signs¹

Physical signs are variable and depend upon the extent of disease.

• Cutaneous features of cirrhosis include:
  • Jaundice
  • Scratch marks secondary to pruritus
  • Spider angiomata/naevi (mainly found on trunk and face)
  • Skin telangiectasias (called "paper money skin")
  • Palmar erythema
  • Bruising
  • Petechiae or purpura
  • Hair loss
  • White nails (horizontal white bands or a proximal white nail plate; sign of hypoalbuminaemia)
  • Finger clubbing
  • Dupuytren's contracture
• Other signs include:
  • Hepatomegaly and a nodular liver
  • Oedema
  • Gynaecomastia and loss of male hair pattern
  • Hypogonadism/testicular atrophy/amenorrhoea (due to the direct toxic effect of alcohol in alcoholic cirrhosis or iron in haemochromatosis)
  • Evidence of type 2 diabetes
  • Kayser-Fleischer ring (a brown-green ring of copper deposit around the cornea, pathognomonic for Wilson's disease)²
• Signs of portal hypertension include:
  • Ascites (can be detected clinically when ≥ 1.5 litres of fluid is present)
  • Caput medusae (veins seen radiating from the umbilicus)
  • Enlarged spleen
• Signs of hepatic encephalopathy:
  • Asterixis (or 'flapping tremor'; suggests hepatic encephalopathy)

To detect asterixis, take the patient's hand and gently hyperextend the wrist and joints of the hand, pushing gently on the tips of the 4 fingers. Ignore the thumb. Hold that position for several seconds and you will feel a slow, clonic flexion-relaxation movement against your hand if asterixis is present.

These will depend to a considerable extent upon clinical suspicion of the aetiology.

Blood tests

• Liver function tests: should include aspartate transaminase (AST), alanine transaminase (ALT), alkaline phosphatase (ALP), bilirubin, gamma-glutamyltransferase (gamma-GT); AST and ALT are raised due to hepatocyte damage; gamma-GT is high in active alcoholics.¹
• Albumin: there is hypoalbuminaemia in advanced cirrhosis.
• Full blood count: occult bleeding may produce anaemia; hypersplenism may cause thrombocytopenia; macrocytosis can suggest alcohol abuse.
• Urea and electrolytes: hyponatraemia may be present (due to increased activity of antidiuretic hormone).¹ Poor renal function may represent hepatorenal syndrome.
• Red cell folate: alcohol abuse is often associated with a diet inadequate in folate.
• Coagulation screen: abnormalities of coagulation are a sensitive test of liver function; prothrombin time is reduced in advanced cirrhosis.¹
• Ferritin: low ferritin may indicate iron deficiency from diet or blood loss; ferritin is raised in haemochromatosis.
• Viral antibody screen: to look for evidence of hepatitis B or C infection.
• Fasting glucose/insulin/triglycerides and uric acid levels: these should be measured if non-alcoholic steatohepatitis is suspected.
• Autoantibody screen: anti-mitochondrial antibodies are a very strong indicator of primary biliary cirrhosis.¹⁰
• Alpha-1-antitrypsin level: to assess for alpha-1-antitrypsin deficiency.
• Caeruloplasmin and urinary copper: to look for Wilson's disease.
• Fasting transferrin saturation and HFE (haemochromatosis C282Y) mutation: along with a raised ferritin these tests can screen for haemochromatosis.

Imaging

• Ultrasound scan of liver and possibly CT or MRI: their main use is to detect complications of cirrhosis such as splenomegaly, ascites or hepatocellular carcinoma.¹
• Chest X-ray: this may show an elevated diaphragm and even pleural effusion (due to the passage of ascitic fluid across the diaphragm).³

Liver biopsy

• Histology is usually needed for the definitive diagnosis of cirrhosis and liver biopsy is the gold standard.¹
• It may also give a clue to the underlying cause.
• Any coagulation defect must be corrected first and blood must be available for transfusion.
• If there are clear signs of cirrhosis such as ascites, coagulopathy, and a shrunken nodular-appearing liver, then confirmation of diagnosis by biopsy may not be necessary.¹

Classification systems for cirrhosis

The Child-Pugh-Turcotte (CPT) classification system is a widely used and validated way to estimate prognosis in those with cirrhosis.¹

A statistical model for end-stage liver disease (MELD) has also been developed to help to predict survival in cirrhosis and to help with timing and allocation of liver transplantation.^11,12

• This depends on the underlying cause. There are separate articles discussing the management of the conditions that can lead to cirrhosis.
• The aim of treatment is to try to delay progression to a higher Child-Pugh-Turcotte (CPT) class which will also hopefully reduce the chance of hepatocellular carcinoma.
• Complications are also treated if and when they arise.
• The most important measure for someone with alcoholic cirrhosis is for them to stop drinking.
• Continued alcohol intake can also increase the rate of progression of cirrhosis from any cause.
• Vitamin supplementation may be needed. Zinc deficiency is common and there is a risk of osteoporosis.³
• Liver transplantation is the ultimate treatment for cirrhosis and end-stage liver disease.¹
• For the future: various antifibrotic drugs have been postulated that may slow down, or even reverse, the fibrotic process in cirrhosis and clinical trials have been carried out/are under way. Stem-cell or hepatocyte transplantation aimed at restoring liver function is also being investigated.¹
• Hepatitis A and B immunisation may also be considered if appropriate.³

If complications develop, the patient should be transferred to a specialised liver unit where there is the expertise to manage the complications and where the patient can also be assessed as to their suitability for liver transplantation.¹

Oesophageal varices

• These can occur as a result of portal hypertension.
• See separate article entitled Oesophageal Varices for more details.

Ascites

• This is a common feature of cirrhosis.
• It is an accumulation of excessive fluid within the peritoneal cavity due to the increased plasma volume (see below) 'spilling over' into the abdominal cavity.³
• The clinical detection of ascites is described in the article Abdominal Examination but much smaller volumes may be detected by ultrasound.
• Its aetiology and management are discussed in the articles Ascites and Ascites Tapping.

Spontaneous bacterial peritonitis

• Ascites may be associated with spontaneous bacterial peritonitis.
• It is thought to be caused by the spread of bacteria across the gut wall and/or haematogenous bacterial spread.³ Escherichia coli is among the most common organisms implicated.³
• This may be prevented by adequately treating ascites and treating those with high neutrophil counts in their ascitic fluid (>250 neutrophils/ml) with empirical intravenous antibiotics and albumin.^1,11
• Patients who survive an episode of spontaneous bacterial peritonitis should receive long-term prophylaxis with oral antibiotics such as norfloxacin, levofloxacin or trimethoprim.^1,11

Hepatic encephalopathy

This is characterised by mental slowing, somnolence, memory loss, asterixis (liver flap) and finally coma. In the late stages, the breath may have the characteristic fetor hepaticus.
• Please refer to the related article on Hepatic encephalopathy.

Hepatorenal syndrome

• This is renal failure in someone with cirrhosis who has no other intrinsic renal disease.¹¹
• There is sodium and water retention, reduced renal blood flow and glomerular filtration rate and reduced urine output.¹¹
• Please refer to the Hepatorenal syndrome article.

Hepatocellular carcinoma

• Cirrhosis is a major risk factor for hepatocellular carcinoma.¹
• The risk varies according to the cause of cirrhosis.
• It is most often associated with cirrhosis caused by hepatitis C infection, followed by cirrhosis caused by hereditary haemochromatosis.¹
• Worldwide, hepatocellular carcinoma as a result of cirrhosis secondary to hepatitis B infection causes a large number of deaths.
• The risk of hepatocellular carcinoma is lower in those with alcoholic cirrhosis (8% 5-year occurrence) or primary biliary cirrhosis (4% 5-year occurrence).¹
• Patients with cirrhosis should be screened for hepatocellular carcinoma.
• The American Association for the Study of Liver Diseases (AASLD) and the European Association for the Study of the Liver (EASL) guidelines recommend at least one screening per year for hepatocellular carcinoma in patients with cirrhosis, using imaging with ultrasonography, triphasic CT, or gadolinium-enhanced MRI.^13,14,15 Screening using serum alpha-fetoprotein is no longer recommended because of its poor sensitivity and specificity.¹
• Hepatocellular carcinoma is discussed in more detail in a dedicated article.

Other complications

Other less common complications can include:

• Cirrhotic cardiomyopathy - there is cardiac hypertrophy and a blunted stress response of the heart. May cause significant problems peri-operatively and mean that liver transplantation may be too dangerous.¹
• Hepatopulmonary syndrome - there is pulmonary arteriolar vasodilation, shunting, and hypoxaemia. Transplantation may reverse this.¹
• Portopulmonary hypertension - an irreversible condition that can occur in those with refractory ascites.¹

• This depends on the underlying cause and the success of the treatment of the underlying cause. Prognosis is discussed in the separate articles for the conditions that can lead to cirrhosis.
• If someone with alcoholic cirrhosis continues to drink alcohol, the rate of decompensation can be rapid.¹

• Worldwide, the most important factor in prevention of cirrhosis is immunisation against hepatitis B.
• There is no vaccine against hepatitis C but some treatments may delay progression and alcohol must be avoided.
• Sensible drinking is essential for everyone and patients should be advised about the recommended limits.
• There are various dedicated articles providing further information about the assessment and management of harmful drinking and alcohol dependence:
  • Alcohol Use Disorders Identification Test (AUDIT)
  • CAGE Questionnaire
  • Alcohol-related Problems
  • Alcoholism - Diagnosis and Assessment
  • Alcoholism and Alcohol Abuse - Management
• Beware of hepatotoxic medications, including herbal remedies.
• Weight reduction and exercise can improve liver function in patients with non-alcoholic steatohepatitis.¹⁶