See also separate article Primary Biliary Cirrhosis.
Cirrhosis is a diffuse hepatic process characterised by fibrosis and the conversion of normal liver architecture into structurally abnormal nodules. Cirrhosis represents the final histological pathway for a wide variety of liver diseases. The progression to cirrhosis is very variable and may occur over weeks or many years.1 Around 80-90% of the liver parenchyma needs to be destroyed before there are clinical signs of liver failure.2 However, there is often a poor correlation between the histological findings and the clinical picture.
The fibrosis causes distortion of the hepatic vasculature and 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.3 Damage to liver cells (hepatocytes) causes impaired liver function and the liver becomes less able to synthesise important substances such as clotting factors and is also less able to detoxify other substances (see also separate article Liver Failure).
Causes of cirrhosis
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.1
- Common causes of cirrhosis include:
- Less common causes include:
- 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 disease.1
- Primary sclerosing cholangitis.
- Venous outflow obstruction in Budd-Chiari syndrome or veno-occlusive disease.1
- Drugs and toxins including methotrexate, amiodarone and isoniazid.1,2
- Congestive heart failure or tricuspid regurgitation (although this is rarely seen now due to improved management).1
- Infections including congenital and tertiary syphilis and schistosomiasis.2
- It is difficult to estimate the exact prevalence of cirrhosis, as previously undiagnosed cirrhosis is often found at postmortem.
- There are an estimated 30,000 people living with cirrhosis in the UK and at least 7,000 new cases being diagnosed each year. The number of people living with both alcoholic cirrhosis and non-alcohol-related cirrhosis seems 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.3
- Hepatitis B is the most common cause in parts of Asia and in sub-Saharan Africa.3
- 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).3
- 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 (NASH):3,8,9
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.
The history should include a thorough enquiry for possible underlying causes of cirrhosis, including a full drug and alcohol history (including over-the-counter drugs, complementary medicines and recreational drugs), risk factors for hepatitis infection, and family history of autoimmune or liver diseases.
Cirrhosis may present with vague symptoms such as fatigue, malaise, anorexia, nausea and weight loss. In advanced, decompensated liver disease, presentation may include:
- Easy bruising.
- Poor concentration and memory.
- Bleeding oesophageal varices.
- Spontaneous bacterial peritonitis.
Physical signs are variable and depend upon the extent of disease.
- Cutaneous features of cirrhosis include:
- Scratch marks secondary to pruritus.
- Spider angiomata/naevi (mainly found on the trunk and face).
- Skin telangiectasias (called 'paper money skin').
- Palmar erythema.
- 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.
- 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).
- 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 ('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 four 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.
- LFTs: 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.3
- Albumin: there is hypoalbuminaemia in advanced cirrhosis.
- FBC: occult bleeding may produce anaemia; hypersplenism may cause thrombocytopenia; macrocytosis can suggest alcohol abuse.
- Renal function tests and electrolytes: hyponatraemia may be present (due to increased activity of antidiuretic hormone).3 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.3
- 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 (NASH) 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.
- Ceruloplasmin 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.
- Ultrasound scan of liver and possibly CT or MRI scan: their main use is to detect complications of cirrhosis, such as splenomegaly, ascites or hepatocellular carcinoma.3
- CXR: this may show an elevated diaphragm and even pleural effusion (due to the passage of ascitic fluid across the diaphragm).1
See separate article Liver Biopsy.
- Histology is usually needed for the definitive diagnosis of cirrhosis and liver biopsy is the gold standard.3
- 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.3
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.3
|Child-Pugh (Child-Pugh-Turcotte) Classification|
|Criterion||Score 1 point||Score 2 points||Score 3 points|
|Serum albumin (g/L)||>35||28-35||<28|
|Serum bilirubin (total)3||<34 μmol/L (<2 mg/dL)||34-50 μmol/L (2-3 mg/dL)||>50 μmol/L (>3 mg/dL)|
|International Normalized Ratio (INR)||<1.7||1.7-2.2||>2.2|
|Ascites||Absent||Controlled medically||Poorly controlled|
|Encephalopathy||Absent||Controlled medically||Poorly controlled|
|A score of 5-6 is class A (life expectancy 15-20 years); a score of 7-9 is class B (life expectancy 4-14 years); a score of 10-15 is class C (life expectancy 1-3 years). This aligns with a perioperative mortality (for abdominal surgery) of 10%, 30%, and 80% respectively.|
The aim of treatment is to delay progression of cirrhosis and to prevent and/or treat any complications of cirrhosis.
- Specific treatment for the underlying cause.
- Ensure adequate nutrition, including calorie and protein intake.
- Alcohol: 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.
- Zinc deficiency is often seen in patients with cirrhosis and treatment with zinc supplements may be helpful.
- Pruritus is a common complaint in cholestatic and non-cholestatic liver diseases. Mild itching complaints may respond to treatment with antihistamines and topical ammonium lactate. Colestyramine is the mainstay of therapy for the pruritus of liver disease. Rifampicin has helped some patients unresponsive to colestyramine. Severe pruritus may require treatment with ultraviolet light or plasmapheresis.
- Patients with cirrhosis may develop osteoporosis and those at risk of osteoporosis should be given preventative treatment. See also separate article Osteoporosis Risk Assessment and Primary Prevention
- Regular exercise should be encouraged and is important to prevent muscle wasting.
- Prophylactic antibiotic use in patients with cirrhosis and upper gastrointestinal bleeding significantly reduces bacterial infections, and seems to reduce all-cause mortality, bacterial infection mortality, rebleeding events, and length of hospitalisation.13
- Patients with chronic liver disease should receive vaccination to protect them against hepatitis A, influenza and pneumococci.
- Drug prescribing: care is essential to avoid any drug that may not be properly metabolised in the presence of liver failure, have an adverse effect on the degree of liver failure or be a cause of drug-induced liver disease. See prescribing in hepatic impairment and the separate article Drug-induced Hepatitis.
- Liver transplantation is the ultimate treatment for cirrhosis and end-stage liver disease. See the separate Liver Transplantation article.3
- 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 underway. Stem-cell or hepatocyte transplantation aimed at restoring liver function is also being investigated.3
- Surveillance of oesophageal varices.
- Surveillance for hepatocellular carcinoma.
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.3
Anaemia, thrombocytopenia and coagulopathy1
- Anaemia may result from folate deficiency, haemolysis, or hypersplenism.
- Thrombocytopenia is usually secondary to hypersplenism and decreased levels of thrombopoietin.
- Coagulopathy results from decreased hepatic production of coagulation factors. If present, cholestasis causes decreased vitamin K absorption, leading to reduced hepatic production of factors II, VII, IX, and X.
- Patients with cirrhosis also may develop fibrinolysis and disseminated intravascular coagulation.
- These can occur as a result of portal hypertension.
- See separate Oesophageal Varices article for more details.
- This is a common feature of cirrhosis.
- It is an accumulation of excessive fluid within the peritoneal cavity due to the increased plasma volume 'spilling over' into the abdominal cavity.1
- The clinical detection of ascites is described in the separate article Abdominal Examination but much smaller volumes may be detected by ultrasound.
- Its aetiology and management are discussed in the separate 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.1 Escherichia coli is among the most common organisms implicated.1
- 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.3,11
- Patients who survive an episode of spontaneous bacterial peritonitis should receive long-term prophylaxis with oral antibiotics such as norfloxacin, levofloxacin or trimethoprim.3,11
- 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 separate Hepatic Encephalopathy article.
See separate article Hepatorenal Syndrome.
- Cirrhosis is a major risk factor for hepatocellular carcinoma. See separate Hepatocellular Carcinoma article.3
- 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.3
- 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).3
- 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.14,15,16 Screening using serum alpha-fetoprotein is no longer recommended because of its poor sensitivity and specificity.3
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.3
- Hepatopulmonary syndrome - there is pulmonary arteriolar vasodilation, shunting, and hypoxaemia. Transplantation may reverse this.3
- Portopulmonary hypertension - an irreversible condition that can occur in those with refractory ascites.3
- Surgery and general anaesthesia have increased risks in the patient with cirrhosis.
- This depends on the underlying cause and on 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.3
- Patients with fulminant hepatic failure have a 50-80% mortality rate unless they receive a liver transplant.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:
- Beware of hepatotoxic medications, including herbal remedies.
- Weight reduction and exercise can improve liver function in patients with non-alcoholic steatohepatitis (NASH).17
- Wolf DC; Cirrhosis, Medscape, Sep 2011
- Heidelbaugh JJ, Bruderly M; Cirrhosis and chronic liver failure: part I. Diagnosis and evaluation. Am Fam Physician. 2006 Sep 1;74(5):756-62. [abstract]
- Schuppan D, Afdhal NH; Liver cirrhosis. Lancet. 2008 Mar 8;371(9615):838-51. [abstract]
- Fleming KM, Aithal GP, Solaymani-Dodaran M, et al; Incidence and prevalence of cirrhosis in the United Kingdom, 1992-2001: a general population-based study. J Hepatol. 2008 Nov;49(5):732-8. Epub 2008 Jun 25. [abstract]
- Leon DA, McCambridge J; Liver cirrhosis mortality rates in Britain from 1950 to 2002: an analysis of routine data. Lancet. 2006 Jan 7;367(9504):52-6. [abstract]
- Poynard T, Bedossa P, Opolon P; Natural history of liver fibrosis progression in patients with chronic hepatitis C. The OBSVIRC, METAVIR, CLINIVIR, and DOSVIRC groups. Lancet. 1997 Mar 22;349(9055):825-32. [abstract]
- Bellentani S, Pozzato G, Saccoccio G, et al; Clinical course and risk factors of hepatitis C virus related liver disease in the general population: report from the Dionysos study. Gut. 1999 Jun;44(6):874-80. [abstract]
- Clark JM; The epidemiology of nonalcoholic fatty liver disease in adults. J Clin Gastroenterol. 2006 Mar;40(3 Suppl 1):S5-10. [abstract]
- Farrell GC, Larter CZ; Nonalcoholic fatty liver disease: from steatosis to cirrhosis. Hepatology. 2006 Feb;43(2 Suppl 1):S99-S112. [abstract]
- Jones DE, James OF, Bassendine MF; Primary biliary cirrhosis: clinical and associated autoimmune features and natural history. Clin Liver Dis. 1998 May;2(2):265-82, viii. [abstract]
- Heidelbaugh JJ, Sherbondy M; Cirrhosis and chronic liver failure: part II. Complications and treatment. Am Fam Physician. 2006 Sep 1;74(5):767-76. [abstract]
- Wiesner R, Edwards E, Freeman R, et al; Model for end-stage liver disease (MELD) and allocation of donor livers. Gastroenterology. 2003 Jan;124(1):91-6. [abstract]
- Chavez-Tapia NC, Barrientos-Gutierrez T, Tellez-Avila FI, et al; Antibiotic prophylaxis for cirrhotic patients with upper gastrointestinal Cochrane Database Syst Rev. 2010 Sep 8;(9):CD002907. [abstract]
- Bruix J, Sherman M, Llovet JM, et al; Clinical management of hepatocellular carcinoma. Conclusions of the Barcelona-2000 EASL conference. European Association for the Study of the Liver. J Hepatol. 2001 Sep;35(3):421-30.
- Llovet JM, Burroughs A, Bruix J; Hepatocellular carcinoma. Lancet. 2003 Dec 6;362(9399):1907-17. [abstract]
- Sherman M, Klein A; AASLD single-topic research conference on hepatocellular carcinoma: Conference proceedings. Hepatology. 2004 Dec;40(6):1465-73.
- Riley TR 3rd, Bhatti AM; Preventive strategies in chronic liver disease: part I. Alcohol, vaccines, toxic medications and supplements, diet and exercise. Am Fam Physician. 2001 Nov 1;64(9):1555-60. [abstract]
Internet and further reading
- British Liver Trust
- Moller S, Henriksen JH; Cardiovascular complications of cirrhosis. Gut. 2008 Feb;57(2):268-78. [abstract]
|© EMIS 2011||Author: Dr Colin Tidy||Reviewer: Dr Adrian Bonsall|
|Document ID: 1964||Document Version: 23||Last Reviewed: 12 Oct 2011|