PubMed Health. A service of the National Library of Medicine, National Institutes of Health.

National Clinical Guideline Centre (UK). Alcohol Use Disorders: Diagnosis and Clinical Management of Alcohol-Related Physical Complications [Internet]. London: Royal College of Physicians (UK); 2010. (NICE Clinical Guidelines, No. 100.)

3Alcohol-related liver disease

Alcohol produces a spectrum of liver injury but only a minority of individuals misuse alcohol, some 20 to 30%, develop cirrhosis; of these, approximately 15% will develop hepatocellular carcinoma as a terminal event. The factors that determine an individual’s susceptibility to develop significant alcohol-related liver injury are largely unknown.

The majority of individuals abusing alcohol will develop fatty change in their liver. This lesion is not in itself harmful and quickly reverses when alcohol is withdrawn. Individuals are usually asymptomatic and generally present incidentally.

Individuals who develop alcohol-related hepatitis may remain asymptomatic and not be detected until they present for other reasons. Alternatively they may present with clear evidence of chronic liver disease such as jaundice, hepatomegaly and fluid retention.

The outcome in individuals with alcohol-related hepatitis is determined by their subsequent drinking behaviour, their gender and by the severity of the disease. The mortality rate in individuals presenting with severe hepatitis may be as high as 40%.

Individuals who develop alcohol-related cirrhosis may remain asymptomatic and come to attention only if inadvertently identified, for example, at an insurance medical examination. Alternatively, they may present with features of hepatocellular failure and portal hypertension, such as jaundice, fluid retention, blood clotting abnormalities, hepatic encephalopathy and variceal haemorrhage.

The outcome for patients with cirrhosis is determined largely by the degree of decompensation at presentation and by the subsequent drinking behaviour. The presence of superimposed alcohol-related hepatitis and the development of hepatocellular carcinoma significantly reduce survival.

The most important management aim is to ensure long-term abstinence from alcohol. Complications such as fluid retention and variceal bleeding have specific therapies. This chapter will review the role of liver biopsy in the investigation of alcohol-related liver disease and the management of alcohol-related hepatitis. The GDG will also consider referral for orthotopic liver transplantation for the treatment of patients with decompensated alcohol-related cirrhosis.

3.1. The role of the liver biopsy

3.1.1. Clinical Introduction

Although the first diagnostic liver biopsy was reported in 1923 75, the procedure has only been used regularly in the last 50 years or so. During this time, a variety of techniques have been used, and the indications have changed as non-invasive diagnostic tests have been introduced.

Liver biopsy can be performed percutaneously, transvenously (with the transjugular approach being the most common) or, rarely, laparoscopically. Of these three techniques, the first two are the ones most commonly performed in patients suspected of having alcohol-related liver injury. Percutaneous liver biopsies themselves can be transthoracic or subcostal and either ultrasound guided or ‘blind’. The transjugular approach is reserved for patients with contra-indications to the percutaneous approach such as ascites or coagulation defects. Unfortunately, these contra-indications are quite common in liver disease, particularly in patients with alcohol-related hepatitis.

The purpose of liver biopsy in alcohol-related liver disease (ALD) is to confirm the diagnosis and stage the disease. Staging is a practice common to all types of liver disease and involves a pathological semi-quantification of the degree of fibrosis or liver scarring. This is absent in a healthy liver and advanced in the case of cirrhosis. With the advent of serum and radiological markers of fibrosis, there is much debate about the role of liver biopsy for this purpose. If non-invasive markers are validated against the histological ‘gold standard’, they make an attractive alternative to an invasive procedure. This debate is one which covers all of hepatology and is not specific to alcohol-related liver disease. As such, the GDG did not include a clinical question around the role of liver biopsy in the staging of alcohol related liver injury. The clinical questions the GDG asked relate to the issue of whether a liver biopsy is required to confirm the diagnosis of ALD or to determine whether there is an active alcohol-related hepatitis.

The diagnosis of alcohol-related liver disease is based on the history (a confirmed history of hazardous or harmful drinking and the absence of other risk factors for liver disease) and examination and certain abnormalities of laboratory variables. Radiology, particularly ultrasound, can also help with the diagnosis. It is important to exclude other liver diseases which could cause the laboratory abnormalities.

In cases where there are laboratory abnormalities and no clear alcohol history or a high index of suspicion of another liver condition there may well be an increased incentive to biopsy. The question is, if one suspects that a patient has alcohol-related liver disease and the clinical work-up has excluded other causes of liver disease, is a biopsy required to confirm the clinical suspicion?

The first clinical question therefore asked and upon which the literature was searched is:

‘What is the accuracy of laboratory and clinical markers versus liver biopsy for the diagnosis of alcohol-related liver disease versus other causes of liver injury?’

Alcohol-related hepatitis (alcoholic hepatitis or AH) is an inflammatory condition of the liver and part of the spectrum of ALD. It is a histological diagnosis with the characteristic features of neutrophil infiltration, hepatocyte ballooning and Mallory bodies. It may arise de novo or superimposed on an already established cirrhosis. Alcohol-related hepatitis may remain silent and its presence may not be marked by any untoward clinical symptoms or signs. However, severe hepatitis presents with the features of hepatic decompensation which include jaundice, gastro-intestinal bleeding, coagulopathy and encephalopathy. The prognosis can be determined using a variety of clinical scores, with the most widely used being Maddrey’s discriminant function (DF), a score based on the bilirubin and prothrombin time. As well as being a useful prognostic marker, this score has also been used to determine which patients will benefit most from specific therapies for AH.

The problem with making clinical decisions based on the prothrombin time and bilirubin level is that these can be abnormal in ALD in patients who do not have AH. This can happen in advanced cirrhosis without superimposed AH, particularly if there is decompensation for another reason such as gastrointestinal bleeding or infection.

Some clinicians will insist upon a liver biopsy before providing specific therapies for severe AH. Others will argue that an experienced clinician will be able to make the diagnosis of AH without biopsy. Again the answer will depend on how frequently the pre-biopsy diagnosis of AH is proven to be incorrect when histology is obtained.

The second clinical question therefore asked and upon which the literature was searched is:

‘What is the safety and accuracy of laboratory and clinical markers versus liver biopsy for the diagnosis of alcohol related hepatitis versus decompensated cirrhosis?’

3.1.2. Clinical methodological introduction

Accuracy of liver biopsy

Studies were included that reported on the accuracy of a clinical judgement based on history, clinical examination and routine laboratory and/or ultrasonography findings or routine laboratory findings. Papers were excluded if they reported on the diagnostic accuracy of individual laboratory findings or whether individual laboratory findings differentiated between clinical conditions.

Nine studies were included in the evidence review 76,77 78 79 80 81 82 83 84.

Level 2+

The details of these studies are summarised in Table 3-1 below. The studies varied considerably with respect to what aspects of clinical management, laboratory findings etc they reported.

Table 3-1. Summary of included studies.

Table 3-1

Summary of included studies.

Seven studies stated that the biopsy was performed blind to the pre-biopsy diagnosis 76 77 78 79 80 81 82. One study did not state if the biopsy diagnosis was performed blind 83. One study involved re-classifying data using a decision making model and therefore can be considered ‘blind’ 84.

Level 2+

It should be noted that the studies may be vulnerable to selection bias, due to the necessary inclusion criteria of liver biopsy. Patients with ALD who undergo biopsy are more likely to have severe disease or more than one medical condition than those who do not undergo biopsy. For example, 113/355 (32%) of patients with presumed decompensated ALD attending a liver unit had liver histology and were therefore eligible for inclusion 76.

Level 1b

One study involved histological diagnosis based on needle biopsy in the majority of patients (101/110, 92%) but also postmortem specimens (7/110, 6%) or explants at liver transplantation (2/110, 2%). 13/110 (12%) tissue specimens were performed prior to their first episode of decompensation ALD (median 5.4 years) and 41/110 (37%) were obtained after the date of first presentation with decompensation (usually to establish alcoholic hepatitis for patients who may require corticosteroid therapy). 56/110 (51%) specimens were obtained more than 31 days (median 15.6 months) after first presentation with decompensation 76.

Level 1b

Safety of liver biopsy

For this question 15 papers were identified that reported on the safety of liver biopsy, reporting on the agreed outcomes, namely death, bleeding, perforation and infection. The populations studied included patients with all forms of liver disease (not just alcohol related liver disease).

Some studies were included if they compared outcomes for different needle types, or for inpatient versus outpatient liver biopsy. For percutaneous liver biopsy, studies were excluded if the number of biopsies was less than 500 and for transjugular/ transvenous less than 100. The large amount of evidence in this area led to this restricted inclusion criteria in order to produce a manageable and meaningful review.

The studies were reported according to the type of biopsy performed:

Percutaneous biopsy

Twelve studies reported on the safety of percutaneous liver biopsy.85–96

Transjugular/ transvenous biopsy

Three studies reported on the safety of transjugular/transvenous liver biopsy.97–99

3.1.3. Clinical evidence statements

Accuracy of liver biopsy

Alcoholic liver disease

In a review of ‘heavy’ drinkers with decompensated liver disease with a presumed diagnosis of ALD (based on alcohol history and extensive non-invasive workup), a total of 104 of the 110 (95%) patients had at least one of the histological features suggestive of ALD: fat, Mallory’s hyalin, neutrophilic infiltrate, and hepatocyte ballooning. These features were more prevalent in tissue obtained within a month after presentation with decompensation than in that obtained before decompensation or more than one month after. In patients with presumed decompensated ALD, other liver diseases are uncommon 76.

Level 1b

The diagnosis of patients with chronically elevated liver enzymes (N=90) on the basis of history, physical examination, laboratory findings and imaging studies was compared with that based on histology. The results are presented in Table 3-2 below 81.

Table 3-2. Summary of results.

Table 3-2

Summary of results.

One study (N=108) reported on the diagnostic value of liver biopsy in alcoholic liver disease. A pre-biopsy clinical diagnosis of alcoholic liver disease (n=35) was confirmed by biopsy in all but one case. The specificity and sensitivity of a pre-biopsy diagnosis of alcoholic liver disease was 98% and 79% 80.

Level 1b

Alcohol-related hepatitis and cirrhosis

One study asked four clinicians differing with respect to professional experience to make a diagnosis based on case history and blind of the biopsy results. They were also asked to rate the certainty of their diagnosis. The results for the diagnostic accuracy (number of patients, total N=200) of clinical compared with histological diagnosis for alcoholic cirrhosis versus no alcoholic cirrhosis are given in Table 3-3 below 79.

Table 3-3. Summary of results.

Table 3-3

Summary of results.

Level 1b

The sensitivity of the clinical diagnosis was 81% (95%CI 73 to 99%)

The specificity of the clinical diagnosis was 89% (95%CI 84 to 95%)

The positive predictive value was 83% (95%CI 75 to 92%)

The negative predictive value was 88% (95%CI 82 to 94%).79

Level 1b

15 patients had a histological diagnosis of alcoholic cirrhosis but were given a negative clinical diagnosis (false-negative):

  • 14/15 had steatosis
  • 1/15 had acute viral hepatitis
  • There was no incorrect clinical diagnosis (0/15) in those patients whom the clinicians were certain of their diagnosis.

Level 1b

13 patients were given a clinical diagnosis of alcoholic cirrhosis but the histology was negative (false positive):

Level 1b

There was no statistical difference for the number of correct or incorrect clinical diagnosis according to professional experience:

  • Chief physician N=3
  • Senior resident N=5
  • Resident N=4
  • Junior resident N=7.79
    Level 1b

The diagnostic accuracy of C-reactive protein (CRP) was reported for alcoholic hepatitis in heavy drinkers (N=101). 29/101 (30%) patients were diagnosed with alcoholic hepatitis on biopsy. Using optimized cut-off values (CRP > 19 mg/L) to discriminate between patients with alcoholic hepatitis and those without these histological lesions, the sensitivity, specificity, positive, negative predictive value and diagnostic accuracy were 41%, 99%, 92%, 81% and 82%, respectively 78.

Level 1b

One study (N=117) reported on whether raised gamma glutamyltranspeptidase (GGT) alone was a sufficient indication for performing liver biopsy. Patients with suspected alcoholic liver disease who had a liver biopsy were categorised in to three groups, namely raised GGT only (17/117, 15%), increased aspartate aminotransferase (AST) with or without raised GGT (34/117, 29%) or widespread abnormal liver function test (66/117, 56%). The following results were reported:

Level 2+

One study (N=89) reported on patients with clinically mild biopsy-proven alcoholic hepatitis for a follow-up period of at least 30 months. Although clinical and laboratory abnormalities were minimal, cirrhosis was present in 38%. A decision rule based on the best predictors of cirrhosis (immunoglobulin A (IgA), prothrombin time and serum glutamic-oxaloacetic transaminase (SGOT)/serum glutamic pyruvic transaminase (SGPT)) was derived to predict the probability of being cirrhotic. The sensitivity was 72% and specificity 88%. 82

Level 1b

One study (N=225) aimed to identify a panel of biomarkers (AshTest) for the diagnosis of alcoholic steato-hepatitis (ASH), in patients with chronic alcoholic liver disease. At a 0.50 cut-off, the sensitivity of AshTest was 0.80 and the specificity was 0.84%. 77

Level 1b

One study selected patients with histologically classified alcoholic liver cirrhosis or alcoholic hepatitis and reclassified them using a likelihood method using 15 or 5 parameters (best combination based on stepwise regression) (see clinical methodology above). The diagnostic accuracy of using the first or second likelihood diagnosis is presented in Table 3-4 below84.

Table 3-4. Diagnostic accuracy.

Table 3-4

Diagnostic accuracy.

Level 1b

Safety of liver biopsy

Mortality
Percutaneous

In the largest study (N=68,276) the mortality rate was 0.009%.86

Level 3

Overall, the mortality rate ranged from 0 to 0.4% (N=10)

Transjugular/ transvenous

Overall, the mortality rate ranged from 0.4 to 0.96% (N=2)

Bleeding
Percutaneous

In the largest study (N=68,276) (total, in patients with cirrhosis) 86:

  • Haemoperitoneum occurred in 0.032% and 0.031% of cases
  • Intrahepatic haematoma occurred in 0.0059% and 0.004% of case
  • Haemobilia occurred in 0.0059% and 0.004% of cases
  • Haemothorax occurred in 0.018% to 0.022% of cases.

Level 3

The overall bleeding rate ranged from 0.06 to 1.7% (N=10).

Bleeding was reported to be higher in patients with increased INR (>1.5), raised bilirubin and lower platelet counts (150 × 109/l).l 90

Level 3

Haemoperitoneum resulting in death was also higher in cirrhotic patients.86

Level 3

Transjugular/ transvenous

The overall bleeding rate ranged from 0.96 to 3.3% (N=2).

One study reported that the majority of patients undergoing transjugular biopsy have contraindications for percutaneous liver biopsy such as coagulation abnormalities and ascites, therefore making them higher risk for bleeding and explaining the variation in bleeding rates between the two different biopsy techniques.97

Level 3

Perforation
Percutaneous

In the largest study (N=68,276) (total, in patients with cirrhosis)86:

  • Pneumothorax occurred in 0.035% and 0.035% of cases
  • Lung puncture occurred on 0.0015% and 0.004% of cases
  • Colon puncture occurred in 0.004% and 0.004% of cases
  • Kidney puncture occurred in 0.003% and 0% of cases
  • Gallbladder puncture 0.012% and 0.013% of cases

Level 3

The overall rate of perforation ranged from 0.06 to 0.5% (N=2).

Transjugular/ transvenous

The overall rate of perforation ranged from 0.6 to 5.8% (N=3)

The study reporting perforation in 5.8% of case consisted of the highest number of patients with cirrhosis (80.8%)99.

Level 3

Infection
Percutaneous

In the largest study (N=68,276) (total, in patients with cirrhosis)86:

  • sepsis occurred in a total of 0.0088% of cases and in 0.018% with cirrhosis.

Level 3

The overall infection rate ranged from < 0.0001% to 0.018% (N=2).

Transjugular/transvenous

Infection rate was not reported in two of the studies 98,99, and one study reported negative blood cultures in patients with pyrexia or rigors.97

Percutaneous biopsy

Table 3-5 shows the results according to date of the study:

Table 3-5. Summary of results.

Table 3-5

Summary of results.

Transjugular biopsy

Table 3-6 shows the results according to the date of the study.

Table 3-6. Summary of results.

Table 3-6

Summary of results.

3.1.4. Health economic methodological introduction

No relevant economic evidence was identified assessing the cost-effectiveness of liver biopsy, and laboratory and clinical markers for the diagnosis of alcoholic liver disease. Costs associated with liver biopsy were presented to the GDG.

3.1.5. Health economic evidence statements

The two most commonly performed approaches for liver biopsy used in alcohol-related liver diseases are the percutaneous and the transjugular approaches. In England and Wales, a liver biopsy procedure can be performed as a day-case intervention or the patient being hospitalized. The cost for liver biopsy procedure is high (for the percutaneous approach, from £1,253 to £4,638 when the patient is hospitalised, considering possible complications and the inpatient stay; and from £437 to £490 when performed as a day-case intervention100. The transjugular approach is not available in all hospital in England and Wales, and patients need to be transferred to another hospital for the procedure. This involves additional costs.

3.1.6. From evidence to recommendations

The GDG recognised that the role of liver biopsy in ALD is not clear and that this is a complicated area. Practice differs throughout the country and the indications, modality and access are not uniform. We have attempted to give guidance in some areas that may affect practice.

First we discussed the safety of liver biopsy. There was a broad range of death and complication rates recorded for liver biopsy. Mortality ranged from 0 – 0.4% for percutaneous and 0.4 – 0.96% for transjugular/transvenous methods. The possible reasons for this broad range of results include the sample size, the period in which the data were collected, the patient populations and the type and the method (needle type, ultrasound guided versus non-ultrasound guided) used. For the outcomes of bleeding, infection and perforation the studies varied considerably with respect to how outcomes were defined. In spite of these differences, there were some large studies, and, on the whole, the GDG accepted the figures for mortality and major morbidity. The GDG felt that the true current figures are likely to be at the lower end of the reported risks for both transcutaneous and transvenous biopsy. Nevertheless, it is important to recognise that there are still mortalities from what is a diagnostic procedure.

The GDG then discussed the issue of sampling error. This is more important with regard to staging than diagnosis but it should be noted that data from twin biopsy studies in non-alcohol-related steatohepatitis (NASH) have shown variability throughout one liver101 calling into question the role of liver biopsy as the ‘gold standard’ diagnostic and staging tool.

The GDG then spent some time discussing the context of the questions. It had been decided that they would not ask a question about the role of liver biopsy in the staging of ALD. This decision had been made for several reasons. First, the question does not map directly to the scope of the guidance. Second, the question is not an alcohol-related liver disease question but more a general hepatology question. Third, studies have not yet been reported determining the role of non-invasive markers of fibrosis (such as fibroscan and serum markers) in ALD. As such the debate would not be informed and it would be difficult to make clear recommendations.

Some members of the GDG felt that it was very difficult to separate diagnosis from staging. They discussed the fact that in the real life clinical scenario, a patient with suspected ALD may have a biopsy for several reasons. This may be partly to exclude other conditions and confirm the diagnosis, partly to stage the disease and partly to demonstrate to the patient the severity of their condition in an effort to persuade them to remain or become abstinent. As such, the questions that have been posed do not answer the question of whether a patient with suspected ALD should have a liver biopsy or not. In order to do this we would need to have explored each of the proposed indications above. Rather, the recommendations will offer guidance as to whether the biopsy should be done for specific indications; to exclude other liver diseases and to confirm alcohol-related hepatitis before treatment.

In this complex area, a further issue was discussed outside of the questions and recommendations. This referred to the investigation of abnormal liver function in patients with a negative liver screen. The paper by Skelly et al102 confirms that a significant proportion of these patients are found to have ALD and admit to drinking when further questioned. These data refer to the question of abnormal liver function with no obvious explanation. An inclusion criterion into this study was the denial of a strong alcohol history. Again, this issue has not been covered by our clinical questions. We recognise that liver biopsy has a role in the investigation of unexplained liver blood test abnormalities, but our question refers to the utility of liver biopsy in patients in whom there is a strong pre-clinical suspicion of ALD (through a typical history, appropriate laboratory tests and compatible imaging).

Studies looking at the accuracy of liver biopsy in the diagnosis of alcohol-related liver disease and non-alcohol-related liver diseases were of low to moderate quality. Patient populations varied considerably, particularly with respect to the non-alcohol liver disease populations (different aetiologies of liver disease).

Overall, if there was a high clinical suspicion of ALD and the liver screen (blood tests done to exclude other causes of liver disease) was negative the biopsy usually revealed ALD and rarely revealed other liver diseases. It must be highlighted again that this did not include patients in whom there was significant ‘pre-biopsy’ clinical doubt about the condition.. On balance, the GDG felt that if these conditions were adhered to, a biopsy was not required to confirm that alcohol was the cause of the liver disease and that there was no indication to do a liver biopsy solely to exclude other causes. When discussing these data, the GDG agreed that the issues surrounding the diagnosis of ALD and the role of a biopsy can be complex and should be made by an experienced clinician. These sentiments are reflected in the guidance.

The GDG recognises that some clinicians will still undertake a biopsy for staging purposes as this can not be assured with certainty from indirect markers. It is particularly important to differentiate those patients with well compensated cirrhosis as they will require long-term surveillance for hepatocellular carcinoma. When the GDG discussed the evidence for the role of liver biopsy in the differentiation of alcohol-related hepatitis from decompensated cirrhosis there were several important themes. The first was that the clinical (pre-biopsy) differentiation of alcohol-related hepatitis from decompensated cirrhosis is inaccurate. While there is a paucity of good studies, a combination of clinical data and GDG experience suggests that the sensitivity and specificity of a pre-biopsy suspicion of alcohol-related hepatitis is between 80 and 90% in those patients that have severe disease. These figures reflect the fact that, without a biopsy, it is difficult to determine which patients should have specific therapy. There are concerns, particularly with corticosteroids, that treatment of a suspected case of alcohol-related hepatitis may be detrimental to the patient if, in fact, they have decompensated cirrhosis. The second major theme of the discussion was that patients in this population often have contra-indications to percutaneous liver biopsy mandating the transjugular approach if biopsy is required. This has increased risks and current access to this procedure is limited to specialist centres.

The GDG further discussed the Ramond and Carithers papers; one of which mandated biopsy prior to trial inclusion (excluding those without alcohol-related hepatitis) while the other did not. The results from both trials were remarkably similar. This was thought to infer that, as long as the patients had the clinical syndrome of recent onset of jaundice with a DF>32 on the background of prolonged heavy drinking, they would get benefit from steroids regardless of the findings of the liver biopsy. Unfortunately, there is no data that can confirm whether patients with this syndrome, that have had a biopsy showing no alcohol-related hepatitis, will benefit from steroids. On balance, it was felt that a biopsy should be done if the clinician felt that it would change their management. That is to say, if the clinician would not give or stop steroids if the biopsy did not show alcohol-related hepatitis, in spite of the presentation and the DF being greater than 32. This will depend on the clinician and how closely the patient resembles those that were included in the relevant trials showing a benefit of steroids. The wording of the recommendation allows for steroids to be started with a presumed diagnosis prior to the biopsy (as the biopsy may take a few days to obtain).

The GDG await the results of a large RCT which compares steroids to placebo, pentoxifylline and dual therapy. Some patients will be biopsied in this study, but the biopsy results will not influence the treatment. When the results of this study are available it should inform a future revision of this recommendation.

3.1.7. Recommendations

R21.

Exclude alternative causes of liver disease in people with a history of harmful or hazardous drinking who have abnormal liver blood test results.

R22.

Refer people to a specialist experienced in the management of alcohol-related liver disease to confirm a clinical diagnosis of alcohol-related liver disease.

R23.

Consider liver biopsy for the investigation of alcohol-related liver disease.

R24.

When considering liver biopsy for the investigation of alcohol-related liver disease:

  • take into account the small but definite risks of morbidity and mortality
  • discuss the benefits and risks with the patient and
  • ensure informed consent is obtained.
R25.

In people with suspected acute alcohol-related hepatitis, consider a liver biopsy to confirm the diagnosis if the hepatitis is severe enough to require corticosteroid treatment.

3.1.8. Research Recommendation

RR5.

What is the cost-effectiveness of the use of liver biopsy in addition to laboratory and clinical markers for the diagnosis of alcohol-related liver disease or alcohol-related hepatitis in patients with suspected alcohol-related liver disease?

3.2. Referral for consideration of liver transplantation

3.2.1. Clinical Introduction

Since initial reports of success in the 1980s, alcohol-related cirrhosis has become an increasingly common indication for orthotropic liver transplantation. Several studies have convincingly demonstrated that the survival of patients transplanted for alcohol-related cirrhosis is comparable to patients with cirrhosis of alternative aetiologies 103. Furthermore, there is no evidence that patients with alcohol-related liver disease have a higher frequency of post-operative complications; although there may be a higher incidence of some specific complications such as post-operative confusion

However, transplantation for this condition still remains controversial, principally due to concerns over the risk of post-transplant recidivism and its effect on outcome and public opinion at a time of increasing donor shortage.

It is beyond the scope of these guidelines to determine the safety, efficacy or cost-effectiveness of liver transplantation for alcohol-related cirrhosis. In addition, it is not within the scope to write guidelines around which patients should be given access to this procedure. The principles of selection to a liver transplant list in the UK have recently been revised 104 and the assessment of co-morbidities and risk of recidivism are the role of the liver transplant units (see Table 3-7). For the nationally agreed guidelines in the context of alcohol-related liver disease go to http://www.uktransplant.org.uk/ukt/about_transplants/organ_allocation/pdf/liver_advisory_group_alcohol_guidelines-november_2005.pdf.

Table 3-7. Variant syndromes and definitions for selection to the adult elective liver transplant waiting list.

Table 3-7

Variant syndromes and definitions for selection to the adult elective liver transplant waiting list.

It is, however, within our scope to address the timing of referral for transplantation. It is likely that patients with alcohol-related cirrhosis are under-represented on transplant waiting lists given the prevalence of the condition compared to other aetiologies of cirrhosis. There are likely to be many reasons for this but awareness of both which patients to refer and when to refer them probably plays a significant role. Whom to refer is determined by the criteria for selection on to a transplant list (refer to Table 3-7), but the GDG believe the timing of referral with regard to the drinking history is critical. Further evidence of the need for recommendations comes from the geographical variability of referral of patients with ALD cirrhosis to liver units across the UK5.

People who are still actively drinking alcohol are not candidates for referral. A period of abstinence is required for a variety of reasons. It is very important to satisfy public opinion (donated organs are a public resource) that the patient is trying to help themselves and there are some data that it associates with post-transplant abstinence but this is controversial. Most importantly, a period of abstinence may allow the liver to recover to a such a degree that transplantation is no longer necessary. Unfortunately, there is still controversy over what period of abstinence is necessary to achieve maximal improvement.

As such, the clinical question upon which the evidence was searched was:

What length of abstinence is needed to establish non-recovery of liver damage, which thereby necessitates referral for consideration for assessment for liver transplant?

3.2.2. Clinical Methodological Introduction

One case series 105 was identified addressing the length of abstinence required to allow improvement in liver function. The study looked at the proportion of patients with severe alcoholic cirrhosis who would need a liver transplant and tried to determine the optimal time needed to evaluate an abstinent patient prior to referral for liver transplantation. All patients recruited for this study were presenting for the first time with severely decompensated alcohol-related cirrhosis, classified as a Child-Pugh class C.

Level 3

Studies were excluded if they looked at the impact of abstinence or continued alcohol consumption on liver disease progression and reported survival as the only outcome.

The reliability of this evidence is poor as it is based on a single case series with a small sample size.

Level 3

3.2.3. Clinical Evidence Statements

Improvement of Liver Function

One study 105 reported on a change in Child-Pugh score from C to B or A as a measure of improved liver function in abstinent patients. Improvement always began within three months if it occurred at all. See Table 3-8 below for a summary of results.

Table 3-8. Summary of results.

Table 3-8

Summary of results.

3.2.4. Health economic methodological introduction

There were no health economic studies found that pertained to the duration of abstinence. However we found one UK health technology assessment evaluating the cost-effectiveness of liver transplant for different patient groups. This study suggested that transplantation was not cost-effective for patients with alcoholic liver disease; if this is true then it could preclude the need for the clinical question. Therefore we reviewed the study to establish the validity of this conclusion.

Longworth 2003106 presented a cost-utility analysis (reporting cost per QALY gained) based on 1995–1996 prospective cohorts of transplanted patients treated for alcoholic liver disease (ALD, n=155), primary biliary cirrhosis (PBC, n=122), and primary sclerosing cholangitis (PSC, n=70). Comparative outcomes for patients not receiving the intervention (liver transplant) were obtained from patient-level pre-transplantation data and from prognostic models, which are based on historical cohorts of patients treated for PBC, ALD, or PSC. A UK NHS perspective was taken for this analysis. Cost and QALYs outcomes were estimated 27 months after a patient was placed on the liver transplant waiting list (approximately 24 months after the transplant procedure). Health outcomes considered for this analysis were survival and health-related quality-of-life (HRQL). HRQL was assessed using the EuroQol EQ-5D classification system, administered to patients at time of listing, at 3-month intervals until transplantation, and then at 3, 6, 12, and 24 months post-transplantation. Costs included were initial assessment for transplantation, hospitalisation, outpatient visits, drugs, blood products, nutrition, physiotherapy sessions, dietician sessions, tests, treatments, and the transplant operation (1999 GBP). Costs were discounted at 6% and QALYs at 1.5%. Extensive sensitivity analyses were undertaken.

3.2.5. Health economic evidence statement

As noted in 3.2.4 above there were no health economic studies found that pertained to the duration of abstinence.

Longworth 2003106 reported incremental cost-effectiveness ratios for liver transplant of £48,000 per QALY gained for ALD patients, £29,000 per QALY gained for PBC patients, and £21,000 per QALY gained for PSC patients. The study considered the initial assessment cost and the time on the waiting list, this being integral components of the UK liver transplantation program. The cost for pre-transplant assessment influenced largely the result for ALD patients: “The larger incremental cost-per-QALY ratio for ALD patients is in part the influence of a larger proportion of ALD patients being considered unsuitable for transplantation after undergoing the assessment process. A reduction in the size of this group of patients, possibly through better evaluation of patients before assessment at transplant centres, would reduce the mean incremental cost-per-QALY ratio for the ALD group”106. In addition, the author mention that if calculated from the time of transplantation (i.e. excluding assessment costs), the incremental cost-effectiveness ratio would be over 50% lower.

This study showed that referring ALD patients for liver transplantation under the 1995–1996 system was not cost-effective and that better referral criteria in primary and secondary care would improve the cost-effectiveness ratio. Hence, the specifics of the referral process for liver transplant for ALD patients might have significant impact on service costs.

An important limitation of the study is that it measured cost-effectiveness of liver transplantation only up to 27 months from time of listing. A lifetime analysis is more appropriate as mortality is impacted by the intervention. In addition, a longer time frame may better cover all costs and benefits related to the intervention, and is likely to increase the QALY gain and improve the cost-effectiveness ratio in favour of transplantation. Furthermore, clinical and resource use data were collected from a 1995–1996 prospective cohort. Discussions with clinical experts suggest that the current UK referral pathway is now much more selective and presumably more cost-effective than it was at the time of the study.

This study has significant limitations. The GDG felt that liver transplantation in its current form is likely to be cost-effective for ALD patients, when long-term benefits and modern selection practices are taken into account.

3.2.6. From evidence to recommendation

Only one small case series was reviewed105 and limited results of interest were reported.

It was found that improvement in liver function, if it occurred at all following abstinence from alcohol, was always evident within three months. This is in agreement with the clinical experience of GDG members.

The paper reported on abstinent (those who declared they were abstinent and confirmed by biological markers), sober (those who decreased their consumption to a non-excessive level: less than 3 units per day for a man, 2 units for a woman; with normalisation of GGT and MCV) and relapsing (one or more periods of abstinence alternating with periods of excessive consumption) people. The GDG agreed that while the study findings were not in completely abstinent people, it was important to include the term ‘abstinent’ be included in the recommendation, particularly as it concerns the allocation of a public resource.

The GDG recognized that there are patients, particularly with alcohol-related hepatitis, that will not survive the three months until they are referred. Currently, alcohol-related hepatitis is a contra-indication to liver transplantation in the UK, and our recommendations are in keeping with the national recommendations for the indications for transplantation. The GDG understand that this may change in the future and this recommendation may need reviewed and adapted should the national recommendations change.

The health economic analysis by Longworth et al. conducted from a UK perspective concluded that liver transplantation was not cost-effective for alcohol liver disease patients, mainly because of the lack of selectivity of the 1995–1996 referral scheme, leading to important additional cost in assessing unsuitable patients for transplantation. The GDG agreed that optimising the selection of patients before assessment at transplant centres is essential, and noted that while the referral process may have led to a reduction in the number of people being inappropriately referred since 1995, there is still room for improvement. In addition, when a referred patient is seen at a transplant centre, there is a tendency to repeat many of the costly tests that have already been carried out, and an improvement in communication between the transplant centres and the referring hospitals may effect substantial cost savings.

3.2.7. Recommendations

R26.

Refer patients with decompensated liver disease to be considered for assessment for liver transplantation if they:

3.3. Corticosteroid treatment for alcohol-related hepatitis

3.3.1. Clinical introduction

Corticosteroids have been the most intensively studied of all treatments for acute alcohol-related hepatitis. They are used as anti-inflammatory agents in this acute inflammatory condition, but it is the potential side-effects, including poor wound healing and susceptibility to infection, that have made these drugs unpopular with some clinicians. These side effects are of particular concern as patients with severe alcohol-related hepatitis often die of sepsis or bleeding.

In order to determine their efficacy, corticosteroids have been delivered intravenously and orally for varying durations at varying doses in RCTs over the last 40 years. Results of these trials have, however, been conflicting and corticosteroids are used with varying frequency for this condition throughout the UK.

Before searching for and discussing trials assessing the efficacy of corticosteroids the GDG agreed that it was important to highlight the population of patients that would be considered for treatment. This is critical to the understanding of the history of corticosteroid use for this condition.

Diagnosis

In many trials the diagnosis of alcohol-related hepatitis was not biopsy-proven. Many hepatologists believe this is a major omission particularly as evidence detailed earlier in this guideline has shown that this diagnosis can not always be made with certainty on clinical and laboratory evidence alone. Furthermore, it is easy to confuse the clinical picture of alcohol-related hepatitis with that of decompensated cirrhosis and these patients may do badly if inadvertently given corticosteroids. Only one corticosteroid treatment trial mandated biopsy but for purposes of this review it was decided not to exclude trials where biopsy was not undertaken in all patients. This was, however, borne in mind during the review of available evidence.

Disease severity

The definition of severity has changed through the years. The presence of hepatic encephalopathy, severe coagulopathy and a high bilirubin were used in early studies. A major advance in the management of alcoholic related hepatitis came when Maddrey described the discriminant function (DF) (calculated from the prothrombin time and bilirubin) which correlates well with mortality107. Since this study, other scoring systems have been used, such as the Glasgow Alcoholic Hepatitis Score (GAHS) and the Model of End stage Liver Disease (MELD) score, but the discriminant function remains the one most widely used in the UK.

It was clear before we asked the clinical question that we would primarily be concentrating on patients with severe disease and we decided to use the Maddrey score of ≥32 to define this.

The GDG therefore asked the clinical question:

‘In patients with acute alcohol-related hepatitis, what is the safety and efficacy of corticosteroids versus placebo?’

‘What is the safety and efficacy of corticosteroids for acute alcohol-related hepatitis?’

3.3.2. Clinical methodological introduction

Eleven RCT’s were identified that compared steroids with placebo or control treatment in patients with alcohol-related severe acute hepatitis 108; 109; 110; 111; 112; 113; 107; 114; 115; 116; 117. One RCT was excluded for using a treatment regimen not currently used in clinical practice (methylprednisolone for 3 days 118. For the sub-group analysis of patients with discriminate function (DF) greater than or equal to 32, data for one study 115 was taken from a paper reporting the results of an individual patients data analysis 119. The studies published before Maddrey introduced the discriminant function criteria were included if the patients could be classified as severe alcohol-related hepatitis e.g., presence of spontaneous encephalopathy.

Level 1+

Table 3-10 below summarises the inclusion criteria and treatment intervention for the included studies. Follow-up ranged from one and a half weeks to one year.

Table 3-10. Summary of inclusion criteria and treatment intervention for included studies.

Table 3-10

Summary of inclusion criteria and treatment intervention for included studies.

The following outcomes were reported:

  • All cause mortality follow-up one month
  • All cause mortality follow-up six months
  • Liver-related mortality follow-up one month
  • Liver-related mortality follow-up six months
  • Rate of Infection
  • Rate of gastro-intestinal bleeding
  • Length of stay

Where available, data is reported for all patients randomised. In some studies, data was available for all randomised patients for some outcomes only.

3.3.3. Clinical evidence statements

Patients with DF ≥ 32, hepatic encephalopathy or severe hepatitis

For a summary of the results see Table 3-11 below. See A.1 for the forest plots.

Table 3-11. Summary of results.

Table 3-11

Summary of results.

Level 1+

Length of stay

Two studies reported on this outcome 114; 110. None of the studies provides confidence intervals and therefore the data could not be entered into a meta analysis. See Table 3-12 for a summary of results.

Table 3-12. Summary of results.

Table 3-12

Summary of results.

Level 1+

Summary

For patients with severe hepatitis, DF ≥ 32 or hepatic encephalopathy, steroids were associated with a significant reduction in the following compared to control:

  • All cause mortality follow-up one month
  • All cause mortality follow-up six months (with significant heterogeneity)
  • Liver-related mortality follow-up one month
  • Liver-related mortality follow-up six months

There were no significant differences between steroids and control for:

Level 1+

Patients with DF ≥ 32

Table 3-13 below summarises the results for patients with DF 32. See A.1 for the forest plots.

Table 3-13. Summary of results.

Table 3-13

Summary of results.

Length of stay

No studies reported on this outcome for this patient population.

Gastrointestinal bleeding

No studies reported on this outcome for this patient population.

Infection

No studies reported on this outcome for this patient population.

Summary

For patients with severed alcoholic hepatitis defined as DF ≥ 32, steroids were associated with a significant reduction in the following compared to control:

There were no significant differences between steroids and control for liver-related mortality follow-up six months.

  • Liver-related mortality follow-up one month and six months

3.3.4. Health economic methodological introduction

No relevant economic analysis was identified assessing the cost-effectiveness of corticosteroids in patients with acute alcohol-related hepatitis. The cost of oral corticosteroids was presented to the GDG.

3.3.5. Health economic evidence statements

The cost of oral corticosteroids is low (few pence per dose [prednisolone]41). The effect of this therapy on the hospital length of stay was not conclusive from the clinical review. With regard to the cost of the drug treatment27 (Table 3-14 the cost-impact of treating patients with acute alcohol-related hepatitis with oral corticosteroids is likely to be marginal.

Table 3-14. Oral corticosteroids.

Table 3-14

Oral corticosteroids.

3.3.6. Evidence to recommendations

The GDG discussed the variability in the trials. The early studies included many patients with mild disease and did not mandate liver biopsy. Some studies used the development of spontaneous hepatic encephalopathy as a marker of severity but this syndrome may develop in patients with decompensated cirrhosis per se. The analysis was restricted to those trials using oral corticosteroids but even within these the periods of treatment were not uniform.

To allow the use of data from before the Maddrey study in 1978 the definition of severity was a DF of 32 or the development of spontaneous hepatic encephalopathy. In addition, the data were analysed using only DF 32 as a marker of severity. This restricted the trials that could be included but the GDG felt it was a more accurate assessment of disease severity.

The GDG noted the efficacy of corticosteroids to reduce one and six month mortality using both definitions of severe disease. In addition there was no significant increase in bleeding or sepsis. The GDG felt that it was appropriate to recommend corticosteroids for patients with severe disease and that the Maddrey score of 32 should be the cut-off to define this. Encephalopathy was not included as a marker of severity in the recommendation as the GDG felt that they did not have robust evidence to recommend corticosteroids to a population with a DF <32 and encephalopathy.

The GDG did not include contraindications to corticosteroids in their recommendation. Gastrointestinal bleeding and active infection are generally considered to be contraindications and have been associated with a poorer outcome. It was agreed by the group that controlled bleeding should not be a contraindication. There is now evidence that if confirmed infection is treated and corticosteroids are started, the outcome is unaffected120. If bleeding or infection are present they should be treated appropriately and corticosteroids should still be used as the treatment for the liver condition.

The GDG are aware of a large RCT about to start in the UK which is comparing steroids with placebo, pentoxifylline and combination treatment. The results of this trial are eagerly awaited and will further inform the debate regarding the best treatment for these patients.

Given the modest drug cost and the substantial reduction in mortality we expect corticosteroids to be highly cost-effective in appropriately selected patients.

3.3.7. Recommendations

R27.

Offer corticosteroidn treatment to people with severe acute alcohol-related hepatitis and a discriminant functiono of 32 or more.

3.4. Nutritional Support for alcohol-related hepatitis

3.4.1. Clinical introduction

Patients with acute alcohol-related liver disease are often malnourished and this has a detrimental effect on survival115. Initial trials with parenteral amino acid therapy yielded conflicting results in improving survival121,122, but more recently the emphasis has switched to providing enteral nutrition. As well as providing calories and protein it is postulated that enteral feeding also provides specific therapy to the underlying inflammatory condition. Alcohol increases gut permeability and the subsequent portal endotoxinaemia can result in lipopolysaccharide-induced cytokine release from liver macrophages and hepatic inflammation. Enteral feeding can improve this gut permeability and this may be a mode through which the therapy can have an impact on liver inflammation and, ultimately, the outcome of an episode of acute alcohol-related hepatitis.

Patients that are fed after a period of reduced nutritional intake are prone to a syndrome known as the refeeding syndrome. This is not covered in this guideline, but recommendations for management are available. It is important to be vigilant for the development of this syndrome in this population of patients.

The exact role of enteral nutrition and whether it should be provided with another treatment or as monotherapy is not clear. Certainly, enteral nutrition is not used as standard therapy in all hospitals in the UK who manage this condition. For this reason, we asked the clinical question:

In patients with acute alcohol-related hepatitis, what is the safety and efficacy of:

  1. enteral nutrition versus standard diet
  2. enteral nutrition versus corticosteroids
  3. enteral nutrition in combination with corticosteroids versus enteral diet

3.4.2. Clinical methodological introduction

Studies were included that reported on the safety and efficacy of enteral nutrition versus standard diet (hospital diet); enteral nutrition versus corticosteroids; enteral nutrition in combination with corticosteroids versus enteral diet in patients with acute alcohol-related hepatitis. Outcomes of interest were survival and adverse events from corticosteroids.

Three RCTs 123–125 and one non-randomised-control trial were included in the review126.

Outcomes reported were mortality, length of stay, weight change and adverse events/side effects, including infections, hepatic encephalopathy, GI bleeding, diarrhoea and ascites.

The studies were reported under the following categories:

  1. enteral nutrition versus standard diet (n=3)
  2. enteral nutrition versus corticosteroids (n=1)

No studies were found that reported on the comparison enteral nutrition in combination with corticosteroids versus enteral diet.

In two studies 124,126 patients allocated to the standard diet group had significantly lower protein, nitrogen balance and calorie intake compared to patients in the enteral nutrition grouppq. Therefore, in effect the comparison could be seen to be adequate enteral nutrition versus inadequate oral nutrition.

Two of the studies 123,124 included patients with alcohol-related cirrhosis.

3.4.3. Clinical evidence statements

Enteral nutrition versus standard diet (n=3)

Mortality

All three studies reported on mortality in patients on enteral nutrition versus standard diet 124–126. The Figure 3-1. shows the meta-analysed results, showing a non-significant (albeit borderline) reduction in mortality with enteral nutrition compared to standard diet.

Level 1+

Length of stay

One study reported on the difference in length of hospital stay between the groups enteral nutrition versus standard diet124.

  • Enteral group: 11 days; standard diet group: 12 days

Level 1+

Weight change

One study reported on weight change in both groups during the two week study period 124, with a significant decrease in weight reported in the standard diet group, and a non-significant decrease in the enteral nutrition group:

  • Enteral nutrition group:74 ± 4 to 72 ± 5 kg, MD 2.00 [−0.57, 4.57], P=0.13
  • Standard diet group:78 ± 3 to 72 ± 4 MD 6.00 [3.47, 8.53], P<0.001

Level 1+

Diarrhoea

Two studies reported on the difference in the number of cases of diarrhoea between the groups enteral nutrition versus standard diet124,125.

One study reported no cases in either group 125.

Level 1+

One study reported a non-significantly lower number of cases of diarrhoea in the enteral nutrition group compared to the standard diet group 124:

  • Enteral nutrition group 5/16 versus Standard diet group 6/15, RR 0.78 (0.30, 2.03), P=0.61

Level 1+

Hepatic encephalopathy

Three studies reported on the difference in the number of cases of hepatic encephalopathy between the groups enteral nutrition versus standard diet 124–126.

One study reported no cases of hepatic encephalopathy associated with the enteral nutrition group 125.

Level 1+

One study 124 reported a significant improvement in the mean grade of encephalopathy over the nine week trial period in the enteral nutrition group:

  • ± 0.3 to 0.4 ± 0.2, MD 0.70 (0.52, 0.88), p<0.001

With significant deterioration in the mean grade of encephalopathy over the 9 week trial period in the standard diet group:

  • 0.7 ± 0.2 to 0.9 ± 0.3, MD −0.20 (−0.38, −0.02), p=0.03
    Level 1+

One study reported on the difference in portal systemic encephalopathy between the groups enteral nutrition versus standard diet 126.

There were a non-significantly higher number of post-therapy cases in the standard diet group compared to enteral nutrition group:

  • Post therapy: Nutritional support group: 4/14 (29); standard diet group: 6/27 (59), RR 1.29 (0.43, 3.82)

There was a significant increase in the number of cases seen pre-therapy compared to post-therapy in the standard diet group:

  • Standard diet group: pre versus post treatment: 21/34 (62) versus 6/27 (59), RR 2.78 (1.31, 5.91), P=0.008

There was a significant reduction in the number of cases seen pre-therapy compared to post-therapy in the enteral nutrition group:

  • Nutritional support group: pre versus post treatment: 13/18 (72) versus 4/14 (29); RR 2.53 (1.05, 6.07), P=0.04
    Level 1+
Ascites

One study reported on the difference in the number of cases of ascites between the groups enteral nutrition versus standard diet 126.

There were a non-significantly higher number of post-therapy cases in the standard diet group compared to enteral nutrition group:

  • post therapy: nutritional support group: 7/14 (50); standard diet group: 16/27 (59), RR 0.84 (0.46, 1.55), p=0.59

There was a significant reduction in the number of cases seen pre-therapy compared to post-therapy in the standard diet group:

  • standard diet group: pre versus post treatment: 29/34 (85) versus 16/27 (59), RR 1.44 (1.02, 2.03), P=0.04

There was a significant reduction in the number of cases seen pre-therapy compared to post-therapy in the enteral nutrition group:

  • nutritional support group: pre versus post treatment: 16/18 (89) versus 7/14 (50); RR 1.78 (1.03, 3.08), P=0.04

Enteral nutrition versus corticosteroids

Mortality

One study reported on mortality (as per protocol) in patients on enteral nutrition versus corticosteroids 123.

There was a non-significant increase in mortality in the enteral nutrition group compared to the corticosteroid group during the treatment period:

  • Treatment period: enteral group: 10/27, corticosteroid group: 9/36; RR 1.48 (0.70, 3.14), P=0.30

There was a non-significant reduction in mortality in the enteral nutrition group compared to the corticosteroid group during the follow up period (1 year or until death):

  • Follow up: enteral group: 1/17, corticosteroid group: 10/27; RR 0.16 (0.02, 1.13), p=0.07
    Level 1+
Length of stay (hospitalization)

One study reported on the difference in the length of stay between patients on enteral nutrition versus corticosteroids 123. There was a non-significant reduction in length of stay in the enteral nutrition group compared to the corticosteroid group:

  • enteral group: 5.3 ± 12.3, corticosteroid group: 8.6 ± 13.6 Mean difference −3.30 (−9.33, 2.73), p=0.28
    Level 1+
Infections

One study reported on infections in patients on enteral nutrition versus corticosteroids 123. There was a non-significant increase in infections in the enteral nutrition group compared to the corticosteroid group:

  • enteral group: 15/35; corticosteroid group: 14/36; RR 1.10 (0.63, 1.93), P=0.73
    Level 1+
Side effects

One study reported on side effects in patients on enteral nutrition versus corticosteroids 123. There was a non-significant increase in side effects in the enteral nutrition group compared to the corticosteroid group:

  • enteral group: 10/35, corticosteroid group: 5/36; RR 2.06 (0.78, 5.41), P=0.14
    Level 1+

Summary

Enteral nutrition versus standard diet (n=3)

Enteral nutrition resulted in a significant improvement in:

  • Mean grade of encephalopathy 124

Enteral nutrition resulted in a significant reduction in:

Enteral nutrition resulted in a non-significant reduction in:

Enteral nutrition versus corticosteroids (n=1)

Enteral nutrition resulted in a non-significant reduction in:

  • Mortality at follow up 123
  • Length of stay 123

Enteral nutrition resulted in a non-significant increase in:

3.4.4. Health economic methodological introduction

No relevant economic analysis was identified assessing the cost-effectiveness of corticosteroids, standard diet, and enteral nutrition in patients with acute alcohol-related hepatitis. The cost of oral corticosteroids was presented to the GDG.

3.4.5. Health economic evidence statements

The cost of oral corticosteroids is low (few pence per dose [prednisolone]27Table 3-14). No cost evidence was found on the use of enteral nutrition in patients with acute alcohol-related hepatitis.

3.4.6. Evidence to recommendations

The GDG accepted the limitations of the clinical evidence. Evidence that enteral nutrition consistently improved outcomes as monotherapy or in combination with other therapies in severe alcohol-related hepatitis was not available.

The studies comparing enteral nutrition to placebo showed reduction in mortality but this was not significant and the meta-analysis although showing a similar trend also failed to reach significance. The heterogeneity of the patient populations complicates the evidence, particularly since the studies concentrating on patients with alcohol-related hepatitis were less convincing than the study in patients with decompensated cirrhosis.

The study comparing enteral nutrition to corticosteroids is not adequate to determine whether there is a difference between the efficacy of corticosteroids and nutrition in the early phase or in follow up but the pattern of mortality during the trial fits conceptually with the action of each treatment and made us ask the question of what enteral nutrition may add to corticosteroid therapy in this population.

The GDG emphasised the importance of further trials in this area and this is reflected in the research recommendation. In addition, the evidence to date, though weak, is in support of the consensus that enteral tube feeding improved outcomes in patients with alcohol-related hepatitis. The GDG considered the ESPEN recommended nutritional supplementation advice of non-protein energy 35–45 kcal/kg/day and protein 1.2–1.5 g/kg/day given orally or enterally or both. This was felt to be appropriate in this setting.

No economic evidence was available assessing the effect of adding enteral nutrition support in patients with alcohol-related hepatitis. As discussed above, the study comparing enteral nutrition to corticosteroids showing no difference in length of stay is not adequate. From studies comparing enteral nutrition and standard diet, the GDG concluded on consensus that enteral nutrition improves outcomes in patient with alcohol-related hepatitis. Given the trend of reduction in mortality from these clinical studies and the likelihood that enteral nutrition improves the patient status from GDG consensus, we believe that enteral nutrition could also have a positive impact on length of stay. Thereby, we consider that the use of enteral nutrition in this patient population is likely to be cost-effective.

3.4.7. Recommendations

R28.

Assess the nutritional requirements of people with acute alcohol-related hepatitis. Offer nutritional support if needed18 and consider using nasogastric tube feeding.

3.4.8. Research recommendations

RR6.

What is the clinical and cost-effectiveness of enteral nutritional support versus normal diet to improve survival in patients with acute severe alcohol-related hepatitis?

Footnotes

l

patients with an INR of 1.5 would not normally be considered for a straight percutaneous biopsy (occasionally ultrasound guided plugged biopsy).

m
n

Corticosteroids are used in UK clinical practice in the management of severe alcohol-related hepatitis. At the time of writing (May 2010), prednisolone did not have UK marketing authorisation for this indication. Informed consent should be obtained and documented.

o

Maddrey's discriminant function (DF) was described to predict prognosis in alcohol-related hepatitis and identify patients suitable for treatment with steroids. It is 4.6 × [prothrombin time – control time (seconds)] + bilirubin in mg/dl. To calculate the DF using bilirubin in micromol/l divide the bilirubin value by 17 (www​.mdcalc.com/maddreys-discriminant-function-for-alcoholic-hepatitis).

p

Kearns 1992: Protein per day: enteral group: 103 6g; standard diet group: 50 4g, p<0.02; average nitrogen balance: enteral group: 480 mmol, standard diet group: 107 mmol; amount of resting energy expenditure (REE) consumed: enteral group: 1.7 0.3 times their REE in first 2 weeks, standard diet group: 0.8 0.1 of their REE in first 2 weeks.

q

Mendenhall 1985: During 30 days hospitalization, calorie intake (kcal/day): standard diet: 2313 121; enteral group: 3236 102, p=0.0001; protein intake (g/day): standard diet: 81.3 4.6; enteral group: 98.3 3.5, p=0.05

18

See ‘Nutrition support in adults: oral nutrition support, enteral tube feeding and parenteral nutrition’. Clinical guideline 32 (2006). Available from www​.nice.org.uk/guidance/CG32

Copyright © 2010, National Clinical Guidelines Centre.

Apart from any fair dealing for the purposes of research or private study, criticism or review, as permitted under the Copyright, Designs and Patents Act, 1988, no part of this publication may be reproduced, stored or transmitted in any form or by any means, without the prior written permission of the publisher or, in the case of reprographic reproduction, in accordance with the terms of licences issued by the Copyright Licensing Agency in the UK. Enquiries concerning reproduction outside the terms stated here should be sent to the publisher at the UK address printed on this page.

Cover of Alcohol Use Disorders
Alcohol Use Disorders: Diagnosis and Clinical Management of Alcohol-Related Physical Complications [Internet].
NICE Clinical Guidelines, No. 100.
National Clinical Guideline Centre (UK).

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