The term cirrhosis was coined by Laennec in 1826. It is from the Greek word scirrhus to describe the orange or tawny surface of the liver seen at autopsy. There is diffuse fibrosis and the development of widespread nodules. The process can take from weeks to many years to develop. Hepatitis C can take 30 to 40 years to progress to cirrhosis.
The disease is often silent and may be unsuspected until diagnosed post mortem.
Worldwide, the largest cause of cirrhosis is hepatitis B with hepatitis C also making a significant contribution. In western societies, alcohol is a major component and in the UK there has been a worrying trend of increasing incidence of injudicious alcohol consumption and alcohol-related disease. According to the report of the Chief Medical Officer for 2001, in 2000 over 4,000 people died from the disease, two thirds of them before their 65th birthday.1 Large rises in death rates from chronic liver disease and cirrhosis have occurred in most age groups. In 45 to 54 year olds, there has been a greater than 4-fold increase amongst men since the early 1970s and a 3-fold increase in women. In 35 to 44 year olds, there has been an 8-fold increase in men and approaching a 7-fold increase in women. The rise in deaths from cirrhosis amongst younger people is of particular concern and, no doubt, related to binge drinking patterns that appear to be common. In 2000, cirrhosis accounted for nearly 500 deaths in men aged 25 to 44 years and nearly 300 deaths in women of this age group.
Reference to this report is made by the British Liver Trust's Alcohol Related Liver Disease Working Party.2
Between 1960 and 2002, the death rate from cirrhosis in men rose by 69% in England and Wales and 106% in Scotland. Amongst women it rose by nearly half.3 The rising trends in deaths from cirrhosis seen in England are in contrast to our European Union neighbours, although Eastern Europe still has a considerable problem. Most European Union countries are showing declining trends, although generally at levels still higher than the current rates in England. Alcohol consumption increases the rate of progression of cirrhosis from any cause. Within various European countries, there is a good correlation between per capita alcohol consumption and death rate from cirrhosis.4 The recent upsurge in binge drinking amongst young women is of particular concern as women are much more susceptible to the adverse effects of alcohol and this is over and above the relative lean body mass. We may expect to see a very significant rise in alcohol related mortality in relatively young women in the near future.
There are many causes including:
- Alcohol abuse, either alone or in combination with other factors, especially hepatitis C
- Chronic hepatitis including from hepatitis B and C
- Congestive heart failure or tricuspid regurgitation although this is rarely seen nowadays due to improved management
- Primary biliary cirrhosis
- Secondary biliary cirrhosis occurs from back-pressure due to chronic biliary obstruction and is rarely seen nowadays
- Hereditary haemochromatosis, although it can also be acquired
- Tyrosinaemia
- Wilson's disease
- Alpha-1-antitrypsin deficiency
- Sarcoidosis
- Type IV glycogen storage disease
- Venous outflow obstruction in Budd-Chiari syndrome or veno-occlusive disease
- Drugs including methotrexate and amiodarone
- Certain herbal remedies.5
Many of these topics have their own article. A significant number of cases will be classified as cryptogenic cirrhosis. This means of unknown aetiology.
Symptoms
Many cases are completely asymptomatic and only discovered on routine blood test. It 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
It may present with complications such as bleeding oesophageal varices or spontaneous bacterial peritonitis.
Take a full drug and alcohol history. Enquire about drugs that have been prescribed, OTC or recreational as well as "alternative remedies" especially herbal.
Signs
Physical signs are also very variable and depend upon the progress of the disease.
- Cutaneous features of cirrhosis include:
- Jaundice
- Spider angiomata (spider naevi)
- Skin telangiectasias (called "paper money skin")
- Palmar erythema
- Bruising
- Petechiae or purpura
- Hair loss
- White nails
- Disappearance of lunulae
- Finger clubbing, especially in hepatopulmonary syndrome
- General Signs:
- Tachycardia
- Raised pulse pressure
- Orthodeoxia (decrease in PaO2 with shortness of breath when patient stands up from lying down)
- Low grade fever
- Oedema
- Gynaecomastia
- Testicular atrophy or amenorrhoea
- Ascites
- Collateral vessels around the umbilicus
- Enlarged spleen
- Nodular liver
- Asterixis (flapping tremor) suggests fulminant hepatic failure
- Increased plantar reflexes
The article on abdominal examination includes description of examination for hepatomegaly andsplenomegaly. 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. This sign tends to suggest quite advanced end stage liver failure and holds a poor prognosis. It has been poetically described as like the patient waving goodbye.
This will depend to a considerable extent upon clinical suspicion of the aetiology:
Blood tests
- FBC, U&E, LFTs are fundamental.
- Red cell folate
- Coagulation screen
- Ferritin.
- Viral antibody screen for Hepatitis B and C
- Autoantibody screen for anti-nuclear factor and anti-smooth muscle. Anti-mitochondrial antibodies are a very strong indicator of primary biliary cirrhosis6
- Alpha-1-antitrypsin level
- Caeruloplasmin and urinary copper for Wilson's disease
- Check alpha feto-protein as a screen for hepatocellular carcinoma
- Occult bleeding may produce iron deficiency anaemia or non-anaemic iron deficiency.
- Low ferritin may indicate iron deficiency from diet or blood loss. Ferritin is raised in haemochromatosis.
- Alcohol abuse is often associated with a diet inadequate in folate but even with normal folate there may be macrocytosis.
- Abnormalities of coagulation are a very sensitive test of liver function.
- Hypersplenism may cause thrombocytopenia.
- Poor renal function may represent hepatorenal syndrome.
Imaging
- U/S liver and possibly CT or MRI
- CXR may show an elevated diaphragm and even pleural effusion
Biopsy
Liver biopsy may be helpful but any coagulation defect must be corrected first and blood must be available for transfusion.
The basis of management is to prevent or retard progression and to treat complications as they arise. The former may involve copper chelation in Wilson's disease or venesection in haemochromatosis. Anti-viral agents may be helpful in hepatitis B7 or C.8 For specific management of specific diseases see the articles about those diseases. Whatever the cause, alcohol must be banned. If diet has been poor this should be rectified and vitamin supplements are often useful. Cholestasis may reduce the absorption of fat soluble vitamins and stores of vitamin K are minimal. Administration by injection may improve clotting factors.
Liver transplantation has become an important strategy in the management of patients with decompensated cirrhosis. Patients should be referred for consideration of liver transplantation after the first signs of hepatic decompensation, with a Child-Pugh score (vide infra) of 7 or more. It may also be performed for hepatocellular carcinoma. Contraindications for liver transplantation include severe cardiovascular or pulmonary disease, active drug or alcohol abuse, malignancy outside the liver, sepsis, HIV or psychosocial problems. Nowadays, survival rates are around 75 to 90% at the end of a year with 70% at 5 years and a good quality of life.9 However, transplantation should be performed before complications such as hepato-renal syndrome or massive ascites develop. With the latter, the 1 year survival rate after transplantation is less than 50%. The optimum timing is when the patient is neither too well nor too ill for transplantation.10
Portal hypertension
This can lead to oesophageal varices that may bleed profusely. It is a condition with a high mortality. The complex issue has evidence based guidelines, laid down by the British Society of Gastroenterology.11 Beta blockade appears to reduce mortality and they suggest that propranolol is the drug of choice. They also suggest that as infection is a major cause of death after bleeding, that ciprofloxacin at 1g daily should be given for a week.
Ascites
Ascites is a common feature of cirrhosis. The clinical diagnosis of ascites is described in abdominal examination but much smaller volumes may be detected by ultrasound. Its aetiology and management are discussed in ascites and ascites tapping.
Ascites may be associated with spontaneous bacterial peritonitis that occurs in 15 to 25% of patients in hospital with ascites. It is commonest with low-protein ascites (<1>Escherichia coli, Streptococcus pneumoniae, Klebsiella species, and other gram-negative enteric organisms. It is diagnosed by the presence of neutrocytosis in ascitic fluid, which is defined as greater than 250 polymorphs per cubic millimetre of ascites, with a positive culture. Culture-negative neutrocytic ascites is more common. Both represent serious infections that carry a 20 to 30% mortality rate. There is a 70% chance of recurrence within a year but prophylactic antibiotics can reduce this to 20%. There is much more in the articles about ascites and ascites tapping.
Gross ascites may push on the diaphragm and impair ventilation and it can push out herniae. Pressure on the gut impairs appetite.
Encephalopathy
Hepatic encephalopathy results from the failure of the liver to detoxify certain substances, especially ammonia, although this is not the only toxin involved.12 It is partly due to toxins from the gut bypassing the liver through anastomotic channels, especially oesophageal varices.
The condition is characterised by mental slowing, somnolence, memory loss, asterixis (hepatic flap) and finally coma. In a late stage the breath may have the characteristic fetor hepaticus.
Treatment includes a low protein diet and laxatives. Encephalopathy may be aggravated or precipitated by shunts or by a GI bleed. The latter is like a sudden high protein meal as blood enters the gut.
A Cochrane review looked at the benzodiazepine receptor antagonist flumazanil13 in hepatic encephalopathy. It concluded that flumazenil had a significant beneficial effect on short-term improvement of hepatic encephalopathy in patients with cirrhosis and a highly favourable prognosis but no significant effect on recovery or survival. Flumazenil may be considered for patients with chronic liver disease and hepatic encephalopathy, but cannot be recommended for routine clinical use.
The treatment of hepatic encephalopathy involves the removal of all drugs that require detoxification in the liver and the reduction of protein in the diet. Restricted protein will generally lower the levels of aminoacids and ammonia in the bloodstream and brain. Limitation to 40 grams of protein a day is the usual advice.Lactulose or neomycin are prescribed to lower amino acid production. Non-meat proteins, such as those in vegetables and milk, are preferred. Certain amino acids are used in treatment, since they are considered less likely to cause mental impairment. Zinc supplements may be beneficial. Emphasis should be on preventing the precipitating factors.12
The scoring system for hepatic encephalopathy is:
Grade 1 - Mild confusion, euphoria or depression, decreased attention, slowing of ability to perform mental tasks, irritability, disorder of sleep pattern such as inverted sleep cycle. Grade 2 - Drowsiness, lethargy, gross deficits in ability to perform mental tasks, obvious personality changes, inappropriate behaviour, intermittent disorientation. Grade 3 - Somnolent but rousable, unable to perform mental tasks, disorientation to time and place, marked confusion, amnesia, occasional fits of rage, speech is present but incomprehensible. Grade 4 - Coma, with or without response to painful stimuli. |
Hepatorenal syndrome
Hepatorenal syndrome represents a spectrum of renal dysfunction with cirrhosis and is caused by vasoconstriction of large and small renal arteries, so reducing renal perfusion.14 NSAIDs may potentiate renal vasoconstriction, and reduce glomerular filtration. They must be avoided in patients with decompensated cirrhosis.
Histological changes in the kidneys are minimal and renal function usually recovers well after liver transplantation. A kidney donated by a patient dying from hepatorenal syndrome functions normally when transplanted into a recipient.
Progression of the disease may be rapid (type 1) or slow (type 2). Type 1 often occurs with rapidly progressive liver failure. Haemodialysis gives temporary respite and liver transplantation is required. In type 2, renal insufficiency is stable or slowly progressive but the patient may develop ascites that is resistant to diuretics.
Diagnostic criteria are:
- Creatinine clearance <40>1.5 mg/dL.
- Urine volume <500>
- Urine sodium <10>
Urine osmolality is greater than plasma osmolality.
Nephrotoxic drugs, including aminoglycosides, should be avoided in patients with cirrhosis. Early hepatorenal syndrome may be treated by aggressive expansion of intravascular volume with albumin and fresh frozen plasma and avoidance of diuretics.
Hepatocellular carcinoma
Cirrhosis is associated with the risk of hepatocellular carcinoma. This risk varies according to cause. It is most often associated with haemochromatosis, alpha-1-antitrypsin deficiency, hepatitis B or C and alcoholic cirrhosis. It is less common in primary biliary cirrhosis and is rare in Wilson's disease. Hepatocellular carcinoma is discussed more fully in its own article.
The Child-Pugh classification system offers important and validated prognosis.
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- Score 5-6 class A
- Score 7-9 class B
- Score 10 or more class C
Patients with a score of 10 or more (Class C) have a 1-year survival around 50%. Patients with Class A or B have a 5-years survival rate of 70% to 80%. Ascites, albumin below 3.2 gm/l, and a recent episode of spontaneous bacterial peritonitis are each associated with a one-year survival of 50% or less.
- Worldwide the most important factor in prevention of cirrhosis is immunisation against hepatitis B.
- There is no vaccine against hepatitis C but some treatments delay progress and alcohol must be forbidden.
- Hepatitis C is becoming more important as a cause of cirrhosis in western societies.
- Sensible drinking is essential and the CMO's report makes depressing reading.
- Beware of hepatotoxic medications, including herbal remedies.
- Preventive care can significantly reduce the progression of liver disease.
- Weight reduction and exercise can improve liver function in patients with fatty liver.15
Document references
- CMO report on the Health of the Nation; DOH (2001)
- Alcohol Related Liver Disease, British Liver Trust
- 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]
- Ramstedt M; Per capita alcohol consumption and liver cirrhosis mortality in 14 European countries. Addiction. 2001 Feb;96 Suppl 1:S19-33. [abstract]
- Stickel F, Seitz HK, Hahn EG, et al;
Z Gastroenterol. 2001 Mar;39(3):225-32, 234-7. [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]
- Borgia G, Gentile I; Treating chronic hepatitis B: today and tomorrow. Curr Med Chem. 2006;13(23):2839-55. [abstract]
- Toniutto P, Fabris C, Pirisi M; Antiviral treatment of hepatitis C. Expert Opin Pharmacother. 2006 Oct;7(15):2025-35. [abstract]
- O'Grady JG; Acute liver failure. Postgrad Med J. 2005 Mar;81(953):148-54. [abstract]
- Merion RM; When is a patient too well and when is a patient too sick for a liver transplant? Liver Transpl. 2004 Oct;10(10 Suppl 2):S69-73. [abstract]
- UK Guidelines on the Management of Variceal Haemorrhage in Cirrhotic Patients, British Society of Gastroenterology (2000); Evidence based guidelines
- Shawcross D, Jalan R; Dispelling myths in the treatment of hepatic encephalopathy. Lancet. 2005 Jan 29-Feb 4;365(9457):431-3. [abstract]
- Als-Nielsen B, Gluud LL, Gluud C; Benzodiazepine receptor antagonists for hepatic encephalopathy. Cochrane Database Syst Rev. 2004;(2):CD002798. [abstract]
- Cardenas A; Hepatorenal syndrome: a dreaded complication of end-stage liver disease. Am J Gastroenterol. 2005 Feb;100(2):460-7. [abstract]
- 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; Support and information
- Wolf DC Cirrhosis eMedicine February 2007.
