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National Guideline Centre (UK). Cirrhosis in Over 16s: Assessment and Management. London: National Institute for Health and Care Excellence (NICE); 2016 Jul. (NICE Guideline, No. 50.)
5.1. Introduction
In the UK, the most common causes of cirrhosis are drinking alcohol at harmful levels, non-alcohol-related steatohepatitis due to diabetes mellitus or metabolic syndrome, and chronic infection with either hepatitis B virus or hepatitis C virus.148 Less common causes include autoimmune liver diseases (autoimmune hepatitis, primary biliary cholangitis or primary sclerosing cholangitis), genetic conditions (haemochromatosis, Wilson's disease, alpha-1 antitrypsin deficiency), prolonged exposure to certain chemicals or medications (amiodarone or methotrexate), Budd-Chiari syndrome or veno-occlusive disease, sarcoidosis and glycogen storage disease.148
People with cirrhosis may present to their primary care physician with non-specific signs and symptoms of the liver disease such as fatigue, loss of appetite or itchy skin, or with the features suggestive of liver failure such as, jaundice and fluid retention manifesting as ankle swelling or abdominal distension. However, many people with cirrhosis remain asymptomatic and hence go unrecognised until their liver begins to fail. The GDG thought that it might be helpful to identify people at risk of having cirrhosis before they developed evidence of liver decompensation and to determine whether there are any validated risk tools that identify these populations.
5.2. Review question 1: What are the risk factors that indicate the populations at specific risk for cirrhosis?
Table 8
Characteristics of review question 1.
5.3. Review question 2: Are there any validated risk tools that indicate the populations at specific risk for cirrhosis?
Table 9
Characteristics of review question 2.
For full details see review protocol in Appendix C.
5.4. Clinical evidence
For question 1, we searched for prospective and retrospective cohort studies investigating the association of the following factors: alcohol intake, BMI, diabetes, hepatitis C and hepatitis B with future development of cirrhosis. Eight studies were included in the review which reported the relative risk of cirrhosis in people with the risk factor compared to people without the risk factor13,15,21,79,103,113,121,197. Evidence from these are summarised in the clinical GRADE evidence profile below. See also the study selection flow chart in Appendix E, forest plots in Appendix K, study evidence tables in Appendix H and exclusion list in Appendix L.
Six studies reported the association of alcohol consumption with the risk of cirrhosis13,15,21,79,113,197. Four studies reported the association of BMI with the risk of cirrhosis15,103,121,197. One study reported the association of diabetes status with the risk of cirrhosis in people with a BMI of 22.5 to <25121. All studies conducted a multivariable analysis and reported an adjusted risk which accounted for the influence of confounding factors, but different variables were included in the analysis between the different studies (see Table 10). Some studies did not account for confounding factors which are specific to cirrhosis (such as hepatitis status) as they were not initially designed to investigate cirrhosis as an outcome. These limitations were taken into account when assessing the risk of bias. Studies reporting relative risks that were not adjusted for any key confounders were not included in the analysis. Studies were not pooled in the analysis because different thresholds were used for analysis of the same outcome in different primary studies.
Table 10
Summary of studies included in the review.
No studies were identified that reported the association of the following risk factors with the risk of cirrhosis in comparison to people without these risk factors: hepatitis C and hepatitis B.
The limitations of the included studies were that some studies reported the risk of cirrhosis taken from death certificates, with death from cirrhosis as the underlying cause. This might be confounded by the fact that people may reduce their alcohol consumption following a diagnosis, and the risk of developing cirrhosis may differ from the risk of death from cirrhosis. For alcohol consumption as a risk factor, some studies looked at alcohol consumption at baseline and then assessed the risk over many years in which no information was collected. Collecting alcohol intake data only once ignores the fact that people change their drinking habits over time, so longitudinal studies that assess alcohol consumption only at baseline may result in misclassification. In the baseline questionnaire, some studies did not question subjects on their past drinking habits, meaning that ex-drinkers who were currently abstaining would have been included in the non-drinking group, therefore biasing the results. These limitations were taken into account when assessing the risk of bias. For question 2, we searched for any validated risk tools that incorporate the risk populations specified in question 1 to indicate the populations at specific risk for cirrhosis (see Appendix C). No validated risk tools encompassing any of the 5 risk factors (obesity, alcohol misuse, viral hepatitis B, viral hepatitis C, type 2 diabetes) were identified from the literature.
5.4.1. Prognostic factor: alcohol consumption
Six studies reported the association of alcohol consumption with the risk of cirrhosis13,15,21,79,113,197. The level of alcohol consumption was categorised differently between the studies. In addition, the studies adjusted for different confounding factors. Therefore, the results were not pooled in the analysis.
Table 11
Prognostic factor: alcohol consumption.
Narrative information
Klatsky 1992113 reported the following information, however 95% CIs were not reported therefore the quality of the evidence could not be assessed. Adjusted HRs (adjusted for age, gender, race, education, BMI, marital status, upper gastrointestinal history, smoking, tea and coffee consumption):
| Hospitalisation for alcohol-related cirrhosis | |
| Drinks/day | |
| <1 drink/day (reference) | HR 1.0 |
| Ex-drinkers | HR 5.4 |
| 1–2 | HR 7.7 |
| 3–5 | HR 18.2 |
| ≥6 | HR 33.1 |
| Hospitalisation for non-alcohol-related cirrhosis | |
| Drinks/day | |
| Lifelong non-drinkers (reference) | HR 1.0 |
| Ex-drinkers | HR 1.2 |
| 1–2 | HR 0.8 |
| 3–5 | HR (analysis not performed because of the small number of cases) |
| ≥6 | HR 0.8 |
| Death from alcohol-related cirrhosis | |
| Drinks/day | |
| <1 drink/day (reference) | HR 1.0 |
| Ex-drinkers | HR 17.1 |
| 1–2 | HR 7.8 |
| 3–5 | HR 21.6 |
| ≥6 | HR 83.4 |
| Death from non-alcohol-related cirrhosis | |
| Drinks/day | |
| Lifelong non-drinkers (reference) | HR 1.0 |
| Ex-drinkers | HR 16.3 |
| 1–2 | HR 7.0 |
| 3–5 | HR 6.4 |
| ≥6 | HR 23.6 |
5.4.2. Prognostic factor: BMI
Four studies reported the association of BMI with the risk of cirrhosis15,103,122,197. The BMI was categorised differently between the studies. In addition, the studies adjusted for different confounding factors. Therefore, the results were not pooled in the analysis.
Table 12
Prognostic factor: BMI.
Narrative information
In addition to the adjusted HRs reported in the table above (BMI overweight 25- <30 and BMI obese ≥30 versus, both versus the reference of normal BMI and adjusted for alcohol as one of the confounding factors) the Ioannou 2003 study103 also reported adjusted HRs for the association of obesity and being overweight with cirrhosis-related hospitalisation or death stratified by alcohol consumption. Among people who did not consume alcohol, they reported a strong association between obesity (adjusted HR 4.10, 95% CI 1.4–11.4) or being overweight (adjusted HR 1.93, 95% CI 0.7–5.3) and cirrhosis-related hospitalisation or death. This association was weaker among persons who consumed up to 0.3 alcoholic drinks/day (adjusted HR 2.48, 95% CI 0.7–8.4 for obesity; adjusted HR 1.31, 95% CI 0.4–4.2 for being overweight), and no association was identified among those who consumed more than 0.3 alcoholic drinks/day (adjusted HR 0.80, 95% CI 0.3–2.1 for obesity; adjusted HR 0.97, 95% CI 0.5–1.8 for being overweight). The cut-off level of 0.3 alcoholic drinks/day was chosen because it was the median level of alcohol consumption among alcohol drinkers. Ioannou 2003103 also reported that when cirrhosis was considered as an any-listed diagnosis instead of as the principal diagnosis, being overweight and obesity were associated with an increased risk for cirrhosis among non-drinkers (adjusted HR 3.0, 95% CI 1.5–6.4 for being overweight; adjusted HR 3.2, 95% CI 1.4–7.3 for obesity), but not among drinkers.
Table 13
Association of obesity and being overweight with cirrhosis-related hospitalisation or death stratified by alcohol consumption (Ioannou 2003).
For the results summarised in Table 12 above, Liu 2010121 reported the association of BMI with risk of cirrhosis-related hospitalisation or death, adjusted for alcohol consumption. This study also reported the association of BMI on the relative risk of cirrhosis in categories of alcohol consumption and diabetes reported at recruitment. They reported that the trend in the relative risk with increasing BMI did not differ significantly between drinkers with increasingly larger consumptions of alcohol (<70, 70 to <150, or ≥150 g/week) or between women who had diabetes or not.
Table 14
Association of BMI with cirrhosis-related hospitalisation or death stratified by alcohol consumption and presence of diabetes (Liu 2010).
5.4.3. Prognostic factor: diabetes status
No studies specifically reported the association of diabetes with the risk of cirrhosis. However, Liu 2010 reported the association of BMI with the risk of cirrhosis in people stratified by diabetes status. As the reference group (without the risk factor) comprised people with a BMI of 22.5 to <25 without diabetes, the risk of diabetes could be assessed in this group (BMI 22.5 to <25).
Table 15
Prognostic factor: diabetes.
Narrative information
Ioannou 2003103 reported little difference in the rates of death or hospitalisation caused by cirrhosis by diabetes mellitus status.
5.5. Economic evidence
No relevant economic evaluations were identified.
See also the economic article selection flow chart in Appendix F.
5.6. Evidence statements
5.6.1. Clinical
Alcohol consumption
- One prospective cohort study of 30,630 people showed that men who drink <1, 8–21, 22–35 or >35 drinks/week are at higher risk of death or a discharge diagnosis of alcohol-related cirrhosis than men who drink 1–7 drinks/week (Low quality evidence). The same study showed that women who drink <1, 8–21, 22–35 or >35 drinks/week are at higher risk of death or discharge with alcohol-related cirrhosis than men who drink 1–7 drinks/week (Very low to Low quality evidence). Only women who drank 1–7 drinks/week had a similar risk of death or discharge with alcohol-related cirrhosis to men who drank 1–7 drinks/week in men (reference). This evidence was of Very Low quality.
- Very Low quality evidence from 1 prospective cohort study of 792 people reported that individuals who had sought help for alcohol addiction, been arrested for drunkenness or had been provided with institutional care by social authorities had lower odds of death or hospitalisation with cirrhosis than people who did not abuse alcohol. Very Low quality evidence from the same study showed that people who self-reported as having alcohol problems and/or daily alcohol consumption had higher odds of death or hospitalisation with cirrhosis than people who did not abuse alcohol.
- Low quality evidence from 1 prospective cohort study of 85,709 people reported lower risk of death due to cirrhosis for people who had an average alcohol intake of 0.1–1.4 or 1.5–4.9 g/day compared to people with an alcohol intake of 0 g/day. The same study showed a higher risk of death from cirrhosis for people who had an average alcohol intake of 5.0–14.9, 15.0–29.9 or ≥30 g/day compared to people with an intake of 0 g/day (Low to Moderate quality).
- Low quality evidence from 1 prospective cohort study of 8,008 people reported an increase in the risk of death from cirrhosis with increasing alcohol consumption.
- One prospective cohort study of 55,917 people showed that men, who currently abstain from drinking alcohol, or have <1, 1, 5–6 or 7 drinking days per week are at higher risk of receiving a diagnosis of alcohol-related cirrhosis compared to men who have 2–4 drinking days per week (Low to Very Low quality evidence). The same study showed that women who currently abstain from drinking alcohol, or have <1, 5–6 or 7 drinking days per week are at higher risk of receiving a diagnosis of alcohol-related cirrhosis compared to women who have 2–4 drinking days per week (Low to Very Low quality evidence). Only women with 1 drinking day per week had a lower risk of a diagnosis of alcohol-related cirrhosis compared to women with 2–4 drinking days per week (Very Low quality evidence).
BMI
- Low quality evidence from 1 prospective cohort study of 30,630 people reported increased risk of death or discharge with alcohol-related cirrhosis for people with a BMI of <20 or >30 compared to people with a BMI of 20–24.
- Low quality evidence from 1 prospective cohort study of 792 people showed increased odds of death or hospitalisation with cirrhosis for individuals who had sought help for alcohol addiction, been arrested for drunkenness or had been provided with institutional care by social authorities and had an elevated BMI (presumed >30), as well as individuals self-reported as having alcohol problems and/or daily alcohol consumption and had an elevated BMI compared to non-obese individuals.
- Low quality evidence from 1 prospective cohort study of 11,465 people reported no changes in risk of death or hospitalisation with cirrhosis for people with a BMI in the overweight category (25- <30) but increased risk for people with a BMI in the obese category (≥30) compared to people with a BMI in the normal category (<25).
- Very Low quality evidence from 1 prospective cohort study of 1,230,662 women reported no difference in risk of death or hospitalisation with cirrhosis for those with a BMI of 25 to <27.5 or 27.5 to <30 compared to women with a BMI of 22.5 to <25. Low quality evidence from the same study showed an increased risk of death or hospitalisation with cirrhosis for women with a BMI of <22.5, 30 to <35, or ≥35 compared to those with a BMI of 22.5 to <25.
Diabetes
- Low quality evidence from 1 prospective cohort study of 1,230,662 women reported increased risk of death or hospitalisation with cirrhosis for women with diabetes (with BMI 22.5 to <25) compared to those without diabetes.
5.6.2. Economic
- No relevant economic evaluations were identified.
5.7. Recommendations and link to evidence
| Recommendation |
|
|---|---|
| Research recommendation |
|
| Relative values of different outcomes | The GDG was interested in the association of the following factors: alcohol intake, BMI, diabetes, hepatitis C and hepatitis B with future development of cirrhosis. The ideal way of predicting an individual's risk of cirrhosis, based on all the individual's risk factors, is to use a validated risk tool. In the absence of such a tool, the GDG looked for evidence on the association of each individual factor with the development of future cirrhosis from prognostic studies. The GDG agreed that this would help identify associations between each risk factor and cirrhosis, and therefore populations who may be at higher risk. However, this evidence cannot predict an individual's risk of cirrhosis in order to determine who should be tested for cirrhosis. |
| Trade-off between clinical benefits and harms | Risk Tools No validated risk tools to predict an individual's future risk of cirrhosis were identified. The GDG were aware of the ‘love your liver’ tool from the British Liver Trust website. However, it was thought that this tool has not yet been validated and no validation studies were identified from the search. It was also thought that this tool predicts the risk of liver disease in general, and not cirrhosis specifically. The GDG discussed that a validated risk tool is the only way to predict an individual's future risk of cirrhosis based on all their risk factors. The GDG made a research recommendation for the development and validation of a risk tool to identify people at highest risk of developing cirrhosis who should be investigated. Risk factors Although a risk tool is the best way to identify an individual's future risk of cirrhosis and identify individuals who should undergo diagnostic testing, knowledge of the risk factors associated with cirrhosis is useful in predicting the likely effect of treatment or avoidance of risk factors, and in planning diagnostic investigations. If the probability of cirrhosis is very low (‘good prognosis’), any adverse effects related to invasive diagnostic tests, even if rare, will play a big part in any decision to perform such tests. If instead the probability of cirrhosis is high (‘bad prognosis’), the impact of new diagnostic information may be large and patients may be ready to accept higher risks of diagnostic investigations. Alcohol consumption Six studies reported association of alcohol consumption and either risk of diagnosis of alcohol-related cirrhosis, or risk of hospitalisation or death from cirrhosis. Studies were not pooled in the analysis because they reported different categorisations for the level of alcohol consumption, and also due to heterogeneity in the confounding factors adjusted for in the analyses. However, the GDG noted the general increase in risk (hazard or odds ratio) associated with an increasing amount of alcohol consumed (above 7 drinks per week, or 5 grams per day) or the number of drinking days (4 or more days per week). They noted that there was a trend towards a higher risk of cirrhosis-related hospitalisation and death in women than men, at the same consumption levels. The GDG discussed the limitations of the prognostic studies, for example only assessing the alcohol consumption at baseline and not taking into account changes in the alcohol consumption over time. This may have resulted in people who were currently abstaining from alcohol being included in the non-drinking group, thereby biasing the results. Although the increased risk of developing cirrhosis associated with an increased alcohol consumption was apparent, due to the differences between studies in how the level of alcohol consumption was measured (that is, drinks per week or number of drinking days per week) it was difficult for the GDG to define a cut-off level of alcohol consumption above which to recommend a diagnostic assessment for cirrhosis. The GDG agreed that it was not necessary for everyone drinking above recommended safe limits to be assessed for cirrhosis. This would result in a large proportion of people who will not develop cirrhosis being tested. The GDG discussed that the people most at risk of developing cirrhosis, and therefore the people who should be tested, are people who fall within the current NHS definition of ‘higher-risk’ drinking: that is, men who drink over 50 units of alcohol per week and women who drink over 35 units of alcohol per week. The GDG agreed that consumption at these levels is associated with an increased risk of developing cirrhosis over time. However, it is important to note that there may be a case for testing in people who have otherwise been identified as potentially having ALD even if their current alcohol consumption is lower than the selected threshold levels, for example those shown incidentally to have abnormal blood tests. The GDG discussed that special consideration should be made in people who may be at higher risk. For example, lower levels of alcohol consumption may lead to increased risk in people of certain ethnic origins (for example those of South Asian origin). However, there was no evidence available on the risk of cirrhosis specifically in this group. The GDG also felt that people with a combination of risk factors should be considered to be at higher risk, for example, people with increased alcohol consumption and hepatitis C. These people should be offered diagnostic assessment for cirrhosis even if their alcohol consumption did not exceed the selected threshold level. BMI Four studies reported the association of BMI with the risk of cirrhosis. Studies were not pooled in the analysis due to the studies reporting different categorisations of BMI, and also due to heterogeneity in the confounding factors adjusted for in the analysis. However, the GDG noted the general increase in risk (hazard or odds ratio) associated with an increase in BMI. The GDG felt that the association of BMI and cirrhosis was not as strong as expected. Being overweight (BMI 25-<30) versus a normal BMI resulted in little increase in risk, with a hazard ratio of 1.08 from one study, and hazard ratios of 1.05 and 1.11 for a BMI of 25-<27.5 and 27.5-<30 respectively from another study. Obesity versus a normal BMI resulted in a larger increase in risk of cirrhosis, with hazard ratios of 1.65 and 2.2 for a BMI >30, and a hazard ratio of 1.49 for a BMI of 30-<35. The GDG noted Table 14 which suggested the added effect of alcohol and BMI and the stratification by diabetes. The reference group for this was low BMI and low alcohol intake. Type 2 diabetes One study reported the association of type 2 diabetes status with the risk of cirrhosis in people with a BMI of 22.5 to <25. There was a higher risk of cirrhosis in people with type 2 diabetes, with an adjusted hazard ratio of 4.29. The GDG agreed that health professionals should be aware of the increased risk of cirrhosis in people with obesity and type 2 diabetes. The GDG noted that ‘Non-alcoholic fatty liver disease (NAFLD): assessment and management’142 has made recommendations on which people to test for hepatic fibrosis and cirrhosis and that cross-reference should be made to this guideline. Hepatitis B and C No evidence was identified that reported the association of hepatitis B or C in comparison to people without these risk factors. The GDG agreed that all people with hepatitis B and C are at a higher risk of cirrhosis and should be tested. |
| Trade-off between net clinical effects and costs | No relevant published economic evidence was identified. ‘Non-alcoholic fatty liver disease (NAFLD): assessment and management’142 has made recommendations to identify people with NAFLD and advanced fibrosis (stage F3). Since an individual must have advanced fibrosis before developing cirrhosis, this group will include all those at risk of progressing to cirrhosis, whilst minimising the number of people with NAFLD needing to be tested for cirrhosis. Since the risk of cirrhosis in people who have obesity or type 2 diabetes comes through their increased likelihood of having NAFLD, and there is no known risk of cirrhosis in people with obesity or type 2 diabetes if they do not also have NAFLD (or an alternative risk factor), then the GDG agreed it was not appropriate to test people with obesity or type 2 diabetes more broadly for cirrhosis, but only the subpopulation identified by ‘Non-alcoholic fatty liver disease (NAFLD): assessment and management’. Having agreed that people with hepatitis B or hepatitis C, and those considered likely to have alcohol-related liver disease have a much higher incidence of cirrhosis than the general population, the GDG agreed that testing these groups would be the most efficient use of resources. These 4 population groups (people with NAFLD, ALD, hepatitis B, hepatitis C) were therefore investigated in the original economic analysis conducted for this guideline, to compare the cost-effectiveness of a variety of diagnostic tests in each of these groups. For each group the diagnostic tests were also compared against an alternative of no testing, and the results showed that testing was cost-effective compared to no testing, thus justifying the decision to test in these 4 population groups. For further results and discussion of the original economic analysis see Chapter 6 and Appendix N. |
| Quality of evidence | Risk tools No clinical evidence was identified. Risk factors The majority of the evidence was of Low or Very Low quality. The main reasons for downgrading the evidence were risk of bias and risk of imprecision. The aspects contributing to the risk of bias are discussed below. All studies conducted a multivariable analysis and reported an adjusted risk which accounted for the influence of confounding factors, but different variables were included in the analysis between the different studies. Some studies did not account for confounding factors which are specific to cirrhosis (such as hepatitis status) as they were not initially designed to investigate cirrhosis as an outcome. These limitations were taken into account when assessing the risk of bias. Studies reported the risk of cirrhosis taken from death certificates or records of hospital admissions, with cirrhosis as the underlying cause. Therefore, the outcomes used by the studies were death or hospitalisation due to cirrhosis, rather than a diagnosis of cirrhosis. This might be confounded by the fact that people may change their alcohol consumption or diet following a diagnosis, and the risk of diagnosis with cirrhosis may differ from the risk of death or hospitalisation due to cirrhosis. For alcohol consumption as a risk factor, some studies looked at alcohol consumption at baseline and then assessed the risk over many years during which no further information on drinking behaviour was collected. Collecting alcohol intake data only once ignores the fact that people change their drinking habits over time, so longitudinal studies that assess alcohol consumption only at baseline may result in a misclassification. In the baseline questionnaire, some studies did not question subjects on their past drinking habits, meaning that ex-drinkers who were currently abstaining would have been included in their non-drinking group, therefore biasing the results. These limitations were taken into account when assessing the risk of bias. For alcohol consumption as a risk factor, the GDG noted that one study which compared 2 models of alcohol abuse (Model 1 and Model 2) had very large confidence intervals associated with the odds ratio (OR) of death/hospitalisation, which accounted for the Very Low quality evidence. Another study reported hazard ratios but without confidence intervals and therefore was included in the narrative only. For BMI as a risk factor, again the GDG noted the very large confidence intervals associated with the HR or OR, which accounted for the Very Low quality evidence. The GDG discussed the applicability of the evidence to a UK population. The GDG noted that the Liu 2010 study was a large 1.3 million population of NHS patients with a large number of events. |
| Other considerations | Research recommendation The GDG agreed that development of a risk tool was a high priority research recommendation. For much of the time, until presentation with jaundice or decompensation, liver disease may remain asymptomatic and silent. The earlier liver disease and even cirrhosis is diagnosed, the better the opportunity to treat, 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 ‘toolkit’ 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. The proposed study should use a 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 a person's risk of developing cirrhosis. |
- Introduction
- Review question 1: What are the risk factors that indicate the populations at specific risk for cirrhosis?
- Review question 2: Are there any validated risk tools that indicate the populations at specific risk for cirrhosis?
- Clinical evidence
- Economic evidence
- Evidence statements
- Recommendations and link to evidence
- Risk factors and risk assessment tools - Cirrhosis in Over 16sRisk factors and risk assessment tools - Cirrhosis in Over 16s
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