P.1. Risk factors and risk assessment tools

Research question: Development of a risk tool to identify people at risk of cirrhosis

Why this is important:

Liver disease in the UK stands out as a glaring exception to the huge improvements in health and life expectancy for chronic disorders such as strokes, heart disease and many cancers. Since 1970 mortality rates for liver disease have increased 400% and in those under the age of 65 have risen almost five-fold. As a result, liver disease now constitutes the third commonest cause of premature death in working age in men and the second in women. The UK has overtaken European countries such as France, Spain and Italy which previously had very high liver mortality.⁷⁸⁰ Of those with cirrhosis 5–10% will go on to develop liver cancer, and the incidence is rising.²¹⁷ In England and Wales it is estimated that some 600,000 people have some form of liver disease, of whom 60,000 people have cirrhosis, leading to 57,682 hospital admissions and 10,948 deaths in 2012.⁵ This represents an increase of 62% in liver disease and 40% in cirrhosis in 10 years. The underlying cause of liver disease is in the main alcohol but there is a rising incidence of obesity, many of whom will have fatty liver disease (1 in 20 in the UK). These patients will have ongoing inflammation and fibrosis (scaring) that will progress over 10–20 years to cirrhosis. Annual deaths from hepatitis C have quadrupled since 1996. The incidence of hepatitis B is rising with the changing population demographics in the UK. There are also patients with autoimmune liver disease who go unrecognised and undiagnosed in the community. Left untreated these patients will progress to end-stage cirrhosis. The resultant cost to the NHS is staggering with estimates in excess of £9 billion per year for alcohol- and obesity-related health problems alone.⁷⁸⁰

Part of the problem is that for much of the time, until presentation with jaundice or decompensation, the liver disease may remain asymptomatic and silent. The earlier liver disease and even cirrhosis is diagnosed, the better the opportunity to intervene, limiting disease progression but in many cases offering a cure. The prevention of progression to end stage liver disease, avoiding complications, reducing the need for investigation, hospitalisation and intervention would have the potential for very large savings for the NHS. The earlier the diagnosis, the greater the potential patient and financial benefit. This is why GPs need a guide or ‘tool kit’ to identify people who are at high risk of having, or developing, advanced liver fibrosis or cirrhosis.

One approach would be to identify a retrospective cohort of people with cirrhosis, and to look at their cirrhosis risk factors. One potential source might be the clinical practice research database (CPRD).⁶ This is a longitudinal database consisting of anonymous computerised primary care records for over 13 million patients in the UK. For many of the practices it is possible to link the CPRD data with HES data.

Patients with any diagnostic code for cirrhosis, oesophageal varices or portal hypertension would be identified in a fixed time period. It would then be possible to go back into the patient records to see if there was any mention in their CPRD record of alcoholism, alcohol abuse, addiction or dependence, or ‘problem drinking’. The alcohol history will be broken down to drinks per week (<1, 1–7, 8–21, 22–35, >35) and alcohol intake (0.1–1.4, 1.5–4.9, 5–14.9, 15–29.9, >30 g/day).

Other demographic and risk factors would be sought including age, sex, viral hepatitis, race and ethnicity, intravenous drug use or substance misuse. Other factors may include autoimmune disease, thyroid, rheumatoid disease, metabolic disease including hypertension, hypercholesterolaemia, BMI and type 2 diabetes mellitus. Also biochemical parameters, including; electrolytes, LFTs, AST, albumin, total protein, globulin fraction, Ferritin, FBC, platelets and coagulation studies.

The proposed study should use multivariate analysis to find the risk factors associated with the outcome of cirrhosis. By weighting the risk factors according to their association with the outcome, a risk tool should be developed to predict an individual's risk of developing cirrhosis. The ultimate risk prediction tool will require validation in a separate cohort (an external validation study).

P.2. Prophylaxis of variceal haemorrhage

Research question: Do non-selective beta-blockers improve survival and prevent first variceal bleeds in people with cirrhosis that is associated with small oesophageal varices?

Why this is important:

Bleeding from oesophageal varices is a major complication of cirrhosis. Approximately half of patients with cirrhosis have oesophageal varices and one-third of all patients with varices will experience bleeding at some point. Despite improvements in the management of acute haemorrhage in recent decades, the 6-week mortality associated with variceal bleeding remains of the order of 10–20%. Risk of variceal bleeding increases with variceal size. Whether non-selective beta-blockers are of benefit as primary prophylaxis in people with cirrhosis and small oesophageal varices has not been adequately studied.

P.3. Transjugular intrahepatic portosystemic shunt (TIPS) versus large-volume paracentesis (LVP) for ascites

Research question: What is the quality of life in people who have had a transjugular intrahepatic portosystemic shunt (TIPS)?

Why this is important:

Prior to TIPS, people may have had several problems resulting from portal hypertension, including variceal bleeding from veins in the stomach, oesophagus, or intestines, ascites or hydrothorax – all of which will have had a detriment effect on their quality of life. TIPS should alleviate these problems, but little is known about the consequential effect on quality of life and any effects that potential problems following TIPS (for example, hepatic encephalopathy, shunt blockages, infection or cardiac problems) have on each person. It is therefore important to assess what benefits TIPS has to the quality of life of people with advanced liver disease.

P.4. Primary prevention of spontaneous bacterial peritonitis (SBP) in people with cirrhosis and ascites

Research question: How frequently does antibiotic resistance occur, and how significant are antibiotic treatment-related complications when antibiotics are used for the primary prevention of spontaneous bacterial peritonitis in people at high risk of having, or developing, cirrhosis?

Why this is important:

Spontaneous bacterial peritonitis (SBP) is the most common serious infection in people with cirrhosis, occurring in 25% of people who develop ascites. It is associated with significant morbidity and mortality rates of 20–40%.

It occurs most commonly in patients with advancing liver disease; approximately 70% of cases occur in people with Child-Pugh class C cirrhosis. Bacterial overgrowth associated with portal hypertension, reduced bowel motility, impairment of the intestinal barrier and reduced host defences result in bacterial translocation from the gut via the mucosa, to the circulation and other extra-intestinal sites. People who have ascites with a low ascitic fluid protein concentration, that is, less than 15 g/litre, are at particularly high risk of developing a first episode of SBP.

People with SBP commonly present with general malaise, pyrexia, abdominal pain, diarrhoea, vomiting, confusion and jaundice although up to 30% of patients may be asymptomatic. Most infections are caused by E. coli, Klebsiella sp., Proteus sp., Enterococcus faecalis and Pseudomonas. Diagnostic paracentesis and blood cultures should be undertaken to confirm or refute the diagnosis, however immediate empirical antibiotic therapy is required to prevent deterioration which may lead to worsening ascites, hepatorenal syndrome, liver failure and death. Hospitalisation, intravenous antibiotic therapy and the supportive care required to manage SBP are associated with significant healthcare costs. Following a primary episode of SBP, recurrence is common and up to 70% of patients relapse within 1 year. Two-year survival is estimated at 20%.

Several oral antibiotics that have been investigated for the prophylaxis of SBP have shown benefits and a significant reduction in the incidence of SBP in people at high risk of having, or developing, cirrhosis. They are, however, associated with antibiotic resistance, adverse reactions and drug interactions which may be important although data are currently lacking.

This GDG found that primary, oral prophylactic antibiotic therapy with ciprofloxacin or norfloxacin is currently more cost-effective than to diagnose and treat SBP in high-risk patients. Treatment should be offered to patients with severe disease (Childs-Pugh B and C) and an ascitic protein concentration of less than 15 g/litre as an adjunct to the management of ascites.

There was however a paucity of good quality, recent evidence regarding the prevalence and consequences of antibacterial resistance which may occur during long-term oral antibiotic therapy when used for the prevention of spontaneous bacterial peritonitis. Antibiotic therapy with broad-spectrum agents suppresses susceptible host commensal organisms allowing resistant pathogens such as Clostridium difficile to proliferate, releasing toxins which may damage the gut wall, exacerbating symptoms of SBP and potentially leading to sepsis and death.

Resistant pathogens emerge in hospital and community treatment settings over time irrespective of the antibiotic prophylaxis used and are a major concern for patients and healthcare providers. Antibiotic therapies currently available may be rendered ineffective and conditions incurable. Presently Hospital Trusts face financial penalties when outbreaks of infection with C. difficile occur. Local antimicrobial therapy guidance and epidemiological resistance patterns may need to be considered. Due consideration also needs to be given to antimicrobial stewardship when prophylactic antibiotic therapy is prescribed. Public Health England (2013) and NICE (2015) have published guidance that recommends the prudent prescribing of antimicrobials to prevent the emergence of resistance.

Prospective, randomised trials specifically in this group, adequately powered to determine optimal treatment, are required. The incidence and consequences of resistance, depending on the antibiotic used, the dose, treatment schedule (continuous, intermittent or cyclical) and duration of therapy need to be determined.

P.5. Volume replacement in hepatorenal syndrome

Research question: What is the most clinically and cost-effective volume replacer for patients with hepatorenal syndrome due to cirrhosis who are also receiving vasoactive drugs?

Why this is important:

Hepatorenal syndrome (HRS) develops in people with cirrhosis with ascites and is characterised by impaired renal function.⁶⁴⁹ Terlipressin, a vasoconstrictor most active in the splanchnic circulation, is used to treat HRS but it is given with a plasma volume expander, which serves to maintain the blood volume and increase the blood oncotic pressure, reducing the movement of free fluid into the peritoneum. Human albumin solution is the recommended intravenous volume replacement during large volume paracentesis⁷² and in patients with SBP, in combination with antibiotics, when the serum creatinine is greater than 1 mg/dL, blood urea nitrogen greater than 30 mg/dL, or total bilirubin greater than 4 mg/dL.⁶⁸³ However, in HRS there are no clinical studies examining the benefits and harms associated with albumin compared with other volume replacers.

People with HRS have a low intravascular volume state and there is general agreement that they require volume expansion in combination with vasopressors. Whilst these people have intravascular depletion, the pathophysiology of decompensated cirrhosis is such that they are also fluid overloaded, but the majority of fluid is outside the vascular compartment. People with decompensated cirrhosis are, therefore, more prone to complications of fluid overload, such as pulmonary oedema if given intravenous fluids. The ideal volume expander to be used in HRS should be able to provide its effect with a minimum of infused fluid (that is, have a high oncotic pressure).

P.6. Management of an episode of acute hepatic encephalopathy

Research question: In people with cirrhosis and an acute episode of hepatic encephalopathy secondary to a clearly identified, potentially reversible precipitating factor, does management of the precipitating event alone improve the hepatic encephalopathy without specific treatment?

Why this is important:

Hepatic encephalopathy is a major complication of cirrhosis. Approximately 50% of people with cirrhosis will develop clinically apparent hepatic encephalopathy at some stage after diagnosis – the risk being around 5–25% within 5 years. Hospital admissions are common and inpatient stays often prolonged. The presence of hepatic encephalopathy is associated with a significant increase in mortality; survival after the first episode is 42% at 1 year and 23% at 3 years.

At present, treatment of hepatic encephalopathy is directed primarily at reducing the production and absorption of gut-derived neurotoxins, particularly ammonia, mainly through bowel cleansing, and the use of non-absorbable disaccharides, such as lactulose, although several other agents such as non-absorbable antibiotics are also used. However, in approximately 50% of people admitted with episodic hepatic encephalopathy there is a clearly defined precipitating factor (for example, infections, gastrointestinal bleeding or overuse of diuretics). Treatment is often challenging and some people may need to be cared for in an intensive care setting, at least initially. The identification and correction of any precipitating events is important as there is evidence that this alone may ameliorate hepatic encephalopathy without recourse to specific therapies. However, this has not been rigorously tested in a randomised clinical trial.