Intended for healthcare professionals

Practice Guidelines

Non-alcoholic fatty liver disease (NAFLD): summary of NICE guidance

BMJ 2016; 354 doi: https://doi.org/10.1136/bmj.i4428 (Published 07 September 2016) Cite this as: BMJ 2016;354:i4428
  1. Jessica Glen, senior research fellow1,
  2. Lefteris Floros, senior health economist1,
  3. Chris Day, professor of liver medicine and honorary consultant hepatologist2,
  4. Rachel Pryke, general practitioner partner3
  5. on behalf of the Guideline Development Group
  1. 1National Guideline Centre, Royal College of Physicians, London NW1 4LE, UK
  2. 2Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne NE2 4HH, UK
  3. 3Winyates Health Centre, Redditch B98 0NR, UK
  1. Correspondence to: C Day chris.day{at}newcastle.ac.uk

What you need to know

  • Screening for non-alcoholic fatty liver disease (NAFLD) in adults is not recommended by the guideline due to lack of evidence

  • Offer children with type 2 diabetes or metabolic syndrome screening for NAFLD using liver ultrasonography

  • Lifestyle modification is the only evidence based management for NAFLD

  • Offer adults with NAFLD screening for advanced liver fibrosis every three years using the enhanced liver fibrosis (ELF) blood test

  • Offer children with NAFLD screening for advanced liver fibrosis every two years using the ELF blood test

There has been a lack of national guidance and care pathways for primary care on when to offer testing for NAFLD. Investigation and referral of suspected NAFLD vary widely. There is currently no licensed treatment for NAFLD, and most people are managed by their general practitioner with a focus on lifestyle advice such as weight loss.

Non-alcoholic fatty liver disease (NAFLD) is a spectrum of disease from fatty liver to non-alcoholic steatohepatitis, fibrosis, and cirrhosis. At the least advanced end of the spectrum, non-alcoholic fatty liver (NAFL) is an excess of fat in the liver (steatosis) present in 20-30% of the general population and is largely asymptomatic.1 2 3 4 Currently, diagnosis of NAFLD is most commonly made through incidental findings, such as ultrasonography for investigation of persistently abnormal liver function tests, when other suspected causes have been ruled out.

In around 5-6% of patients with NAFL only the condition progresses to non-alcoholic steatohepatitis (NASH), fibrosis, or cirrhosis (see fig 1).5 In this small group there is a risk of death from liver failure or hepatocellular carcinoma, or needing a liver transplant.1 The number of hospital admissions for liver damage at the more severe end of the NAFLD spectrum, fibrosis and cirrhosis, are increasing every year.6

Figure1

Fig 1 Spectrum of non-alcoholic fatty liver disease (NAFLD)

This article summarises the most recent recommendations from the National Institute for Health and Care Excellence (NICE) on the assessment and management of NAFLD.7

Recommendations

NICE recommendations are based on systematic reviews of best available evidence and explicit consideration of cost effectiveness. When minimal evidence is available, recommendations are based on the Guideline Development Group’s experience and opinion of what constitutes good practice.

Assessment of non-alcoholic fatty liver disease (NAFLD)

Figure 2 outlines the assessment of NAFLD in primary care.

Figure2

Fig 2 Assessment of non-alcoholic fatty liver disease (NAFLD) in primary care

Diagnosing NAFLD

Alternative causes of fatty liver

Other causes of fatty liver (hepatic steatosis) that must be ruled out before a diagnosis of NAFLD can be made:

  • Excessive alcohol use (daily alcohol consumption ≥30 g for men and ≥20 g for women)

  • Side effects of certain medications

  • Hepatitis C virus infection

  • Some endocrine conditions

The gold standard for diagnosis of NAFLD is liver biopsy, which is too high risk for routine investigation in a population of patients who are likely to be asymptomatic.

The Guideline Development Group (GDG) hypothesised that if a simple, cost effective, non-invasive test was available to identify NAFLD, people could be identified early to ensure adequate monitoring and timely attempts to prevent progression to advanced disease endpoints.

However, there was no evidence to support non-invasive testing for NAFLD in adults, including those with risk factors such as type 2 diabetes or metabolic syndrome. Routine liver function blood tests are not sensitive for the detection of NAFLD, and ultrasonography is not cost effective.

  • Be aware that NAFLD is more common in people who have:

    • Type 2 diabetes or

    • Metabolic syndrome.

      [Based on low to moderate quality evidence from observational studies]

  • Take an alcohol history to rule out alcohol related liver disease. See also NICE’s cirrhosis guideline.8 [Based on the experience and opinion of the Guideline Development Group (GDG)]

  • Do not use routine liver blood tests to rule out NAFLD. [Based on low quality evidence from diagnostic observational studies]

Diagnosing NAFLD in children and young people

Estimates of the prevalence of NAFLD in children are lower than in the general population (7-10%), increasing to 30% in obese paediatric populations.9 10 11

  • Offer a liver ultrasonography scan to test children and young people for NAFLD if they:

    • Have type 2 diabetes or metabolic syndrome and

    • Do not misuse alcohol.

      [Based on the experience and opinion of the GDG]

  • Offer referral to children with suspected NAFLD to a relevant paediatric specialist in hepatology in tertiary care. [Based on the experience and opinion of the GDG]

  • Diagnose children and young people with NAFLD if ultrasonography shows they have fatty liver and other suspected causes of fatty liver have been ruled out. [Based on the experience and opinion of the GDG]

  • Offer liver ultrasonography to retest children and young people for NAFLD every three years if they have a normal ultrasound scan and type 2 diabetes or metabolic syndrome and do not misuse alcohol. [Based on very low to moderate quality evidence from observational studies and the experience and opinion of the GDG]

Management of people with NAFLD

Adults and young people identified with NAFLD through incidental findings can continue to be managed in primary care. The only evidence based management for people with NAFLD is lifestyle modification. The recommendations for pharmacological treatment are limited to those with advanced fibrosis. The GDG considered the use of probiotics and found insufficient evidence to make a recommendation either way.

Lifestyle modifications for NAFLD

  • Manage people with NAFLD who are overweight or obese in line with the recommendations on physical activity and diet in NICE’s obesity and preventing excess weight gain guidelines.12 13 [Based on the experience and opinion of the GDG]

  • Explain to people with NAFLD that physical activity may reduce liver fat content independently of weight reduction. [Based on very low quality evidence from randomised studies]

  • Consider the lifestyle interventions in NICE’s obesity guideline13 for people with NAFLD regardless of their body mass index. [Based on very low to moderate quality evidence from randomised studies and the experience and opinion of the GDG]

  • Do not offer omega-3 fatty acids to adults with NAFLD because there is not enough evidence to recommend their use. [Based on moderate to high quality evidence from randomised studies]

  • Explain to people with NAFLD who drink alcohol the importance of staying within the national recommended limits for alcohol consumption. [Based on the experience and opinion of the GDG]

People with NAFLD who are taking statins

  • Advise people with NAFLD to keep taking statins.

  • Consider stopping statins only if liver enzyme levels double within three months of starting statins, including in people with abnormal baseline liver blood results.

    [Based on the experience and opinion of the GDG]

Assessment for advanced liver fibrosis in people with NAFLD

There was no strong evidence base to support a specific non-invasive test for identifying non-alcoholic steatohepatitis in patients with NAFLD.

Severe liver fibrosis has consistently been shown to indicate a poor prognosis in people with NAFLD.4 5 14 15 Therefore, people with advanced fibrosis require the closest monitoring and have the most to gain from pharmacotherapy slowing or reversing the condition. Of currently available non-invasive tests for identifying NAFLD patients with fibrosis, the enhanced liver fibrosis (ELF) blood test (see box) was found to be most cost effective in identifying patients with advanced liver fibrosis (stages 3 and 4).

Enhanced liver fibrosis (ELF) blood test

The ELF test is a blood test used to measure liver damage. The test uses an algorithm of three serum biomarkers found in the blood to calculate an ELF score:

  • Hyaluronic acid

  • Procollagen III amino terminal peptide

  • Tissue inhibitor of metalloproteinase 1.

Identifying people with advanced liver fibrosis

  • Do not use routine liver function blood tests to identify advanced liver fibrosis in people with NAFLD. [Based on very low to moderate quality evidence from diagnostic observational studies]

  • Offer testing for advanced liver fibrosis to all people incidentally identified with NAFLD using the ELF blood test. [Based on very low to low quality evidence from diagnostic observational studies]

  • Diagnose people incidentally identified with NAFLD with advanced liver fibrosis if they have an ELF blood test score or ≥10.51. [Based on very low to low quality evidence from diagnostic observational studies]

  • Offer retesting for advanced liver fibrosis for people with an ELF blood test score <10.51:

    • Every three years for adults

    • Every two years for children and young people.

      [Based on very low to moderate quality evidence from observational studies and the experience and opinion of the GDG]

  • Refer adults and young people diagnosed with advanced liver fibrosis to a relevant specialist in hepatology. [Based on the experience and opinion of the GDG]

  • Explain to people with an ELF blood test score <10.51 that:

    • They are unlikely to have advanced liver fibrosis

    • Reassessment for advanced liver fibrosis every three years for adults and every two years for children and young people is sufficient for regular monitoring

    • No interim tests are needed.

      [Based very low to moderate quality evidence from observational studies and the experience and opinion of the GDG]

Pharmacological treatment in people with advanced liver fibrosis

  • Adults, children, and young people with advanced liver fibrosis should be managed within secondary or tertiary care, and pharmacological treatment can be considered in this setting. In secondary care settings only, consider pioglitazone or vitamin E for adults with advanced liver fibrosis, whether or not they have diabetes. [Based on low to high quality evidence from randomised studies]

  • Before prescribing pioglitazone or vitamin E, take into account any comorbidities that the person has and the risk of adverse events associated with these conditions. [Based on low to high quality evidence from randomised studies and the experience and opinion of the GDG]

  • In tertiary care settings only, consider vitamin E for children and young people with advanced liver fibrosis, whether they have diabetes or not. [Based on moderate to high quality evidence from randomised studies]

  • Offer to retest people with advanced liver fibrosis two years after they start a new pharmacological therapy to assess whether treatment is effective. [Based on the experience and opinion of the GDG]

  • Consider using the ELF blood test to assess whether pharmacological therapy is effective. [Based on the experience and opinion of the GDG]

  • If an adult’s ELF blood test score has risen, stop either vitamin E or pioglitazone and consider switching to the other pharmacological therapy. [Based on the experience and opinion of the GDG]

  • If a child or young person’s ELF blood test score has risen, stop vitamin E treatment. [Based on the experience and opinion of the GDG]

Monitoring adults and young people over 16 for cirrhosis

  • Monitor adults and young people over 16 years old with NAFLD and advanced liver cirrhosis in line with NICE’s cirrhosis guideline.8 [Based on the experience and opinion of the GDG]

NAFLD as a risk factor for extra-hepatic (non-liver related) conditions

The GDG did not think it appropriate to recommend that any specific people should receive additional assessment or care for conditions associated with NAFLD. Instead they recommended that clinicians be aware of the additional risk posed by NAFLD for the following conditions.

  • Be aware that NAFLD is a risk factor for type 2 diabetes, hypertension, and chronic kidney disease. [Based on very low to low quality evidence from observational studies]

  • Be aware that in people with type 2 diabetes, NAFLD is a risk factor for atrial fibrillation, myocardial infarction, ischaemic stroke, and death from cardiovascular causes. [Based on very low to low quality evidence from observational studies]

Implementation

The GDG hope the recommendations in this guideline will reduce unnecessary testing and target active management for those at highest risk of advanced disease.

  • The GDG acknowledge this may lead to the identification of most people with non-alcoholic steatohepatitis and advanced fibrosis at the expense of missing some affected people

  • Conducting an ELF test to assess the severity of disease in those with NAFLD requires a single blood test that can easily be sent from primary care for analysis

  • Additional resources may be necessary if healthcare professionals wish to audit their existing patients for incidental findings of fatty liver change in order to offer ELF blood testing for advanced fibrosis.

Guidelines into practice

  • Have your patients with fatty liver had an alcohol history taken?

  • Have your patients with NAFLD had an ELF blood test to assess fibrosis risk?

How patients were involved in the creation of this article

Patients were not involved in the creation of this summary article. However, committee members involved in this guideline included lay members who contributed to the formulation of the recommendations summarised here. Patient organisations were among the registered stakeholders who were consulted at both scoping and development stages.

Further information on the guidance

Methods

The guideline was developed using standard National Institute for Health and Care Excellence (NICE) guideline methodology (www.nice.org.uk/article/pmg20/chapter/1%20introduction%20and%20overview). The Guideline Development Group (GDG) developed clinical questions, collected and appraised clinical evidence, and evaluated the cost effectiveness of proposed interventions and management strategies through literature review and economic analysis. Quality ratings of the evidence were based on GRADE methodology (www.gradeworkinggroup.org). These relate to the quality of the available evidence for assessed outcomes rather than the quality of the clinical study. Where standard methods could not be applied, a customised quality assessment was done. These were either presented as a narrative summary of the evidence or in customised GRADE tables (for example, for observational studies). Customised quality assessment was done for the diagnostic meta-analysis conducted on the accuracy of non-invasive tests for non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis, and advanced fibrosis; for the prognostic reviews on risk factors for NAFLD, monitoring of NAFLD, and NAFLD as a risk factor for extra-hepatic conditions.

A health economic model was developed, under the guidance of the GDG, to compare the cost effectiveness of different testing strategies for the diagnosis of steatosis and advanced fibrosis. The model also examined who to test and optimal testing frequencies.

The draft guideline went through a rigorous review process in which stakeholder organisations were invited to comment; the GDG took all comments into consideration when producing the final version of the guideline.

The guideline is available in three formats: a short version; a full version (including all evidence, www.nice.org.uk/guidance/ng49/evidence); and information for the public for people who have NAFLD, their families and carers, and the general public (www.nice.org.uk/guidance/NG49/ifp/chapter/Non-alcoholic-fatty-liver-disease-the-care-you-should-expect).

A formal review of the need to update a guideline is usually undertaken by NICE after guideline publication.

Future research
  • Which non-invasive tests are most accurate in identifying NAFLD in adults with type 2 diabetes or metabolic syndrome?

  • Which of the most accurate tests are also cost effective?

  • Which non-invasive tests most accurately identify non-alcoholic steatohepatitis in people with NAFLD?

  • Which non-invasive tests most accurately diagnose NAFLD and advanced liver fibrosis in children and young people?

  • What is the clinical and cost effectiveness of probiotics to treat NAFLD in adults, young people, and children?

  • What is the clinical and cost effectiveness of pharmacological therapy in children and young people with advanced liver fibrosis?

Footnotes

  • The members of the committee were Christopher Byrne, Chris Day (chair), David Fitzmaurice, Irene McGill, Kevin Moore, Benjamin Mullish, Philip Newsome, Tanja Pardela, Rachel Pryke, Jane Putsey, Indra van Mourik and Bronwen Williams. Expert group members were: Ashley Guthrie, Jill Johnson, Roy Sherwood, Dina Tiniakos, and Michael Trenell. The technical team at the National Guideline Centre included Joanna Ashe, Kate Ashmore, Serena Carville, Angela Cooper, Lefteris Floros, Jessica Glen, Martin Harker, Qudsia Malik, Amelia Unsworth, Claire Wallnut, Natalie Wood and Giulia Zuodar.

  • Contributors: JG drafted the summary, and all authors were involved in writing further drafts and reviewed and approved the final version for publication. CD is the guarantor.

  • Funding: The National Guideline Centre was commissioned and funded by the National Institute for Health and Care Excellence to write this summary.

  • Competing interests: We declare the following interests based on NICE's policy on conflicts of interests (available at www.nice.org.uk/Media/Default/About/Who-we-are/Policies-and-procedures/code-of-practice-for-declaring-and-managing-conflicts-of-interest.pdf): RP has received payment from Janssen Cilag (talks on obesity) and Ethicon (manning a stand on bariatric surgery at the 2014 RCGP conference), and programme funding from Nurtricia and Public Health England on behalf of the RCGP; has been appointed a current NICE fellow; and is a coauthor of a Lancet Commission report on liver disease in the UK. CD is a member of data monitoring committees for GSK and Genfit, a non-executive director of Newcastle Upon Tyne Hospitals NHS Foundation Trust, and a board member of HB Innovations. The authors’ full statements can be viewed at www.bmj.com/content/bmj/354/bmj.i4428/related#datasupp and at www.nice.org.uk/guidance/ng49/documents/committee-member-list.

References

View Abstract

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