Drs Rachel Pryke and Iain Brew (pictured) discuss NICE guidance on liver disease and cirrhosis, and the importance of making a diagnosis before the onset of complications

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Read this article to learn more about:

  • risk factors and their associated mechanisms in progressive liver disease
  • identifying patients with non-alcoholic fatty liver disease and distinguishing between cases that follow a benign path and those that are likely to progress to cirrhosis
  • monitoring for complications that can arise in patients with cirrhosis.

Key points

GP commissioning messages

A t risk of causing dismay at yet another 'disease silo' for GP action, the statistics for liver disease make alarming reading. Unlike mortality trends for other major chronic conditions, such as heart disease and stroke, the mortality rate for liver disease has risen significantly over the last 40 years.1 The number of liver-related deaths increased 400% between 1970 and 2010, and liver disease is the third commonest cause of premature death in the UK. Worryingly, many deaths are in younger patients (aged 18–65 years) where mortality rates increased by almost 500% during the same period.1 This increase is largely attributed to changes in alcohol consumption, but is also increasingly due to obesity-related liver disease.1

Liver disease presents late and has long been considered a secondary care condition, but changes in our understanding of shared risk factors, streamlined investigative pathways, and the long latent phase of liver disease have created huge potential for community prevention approaches; therefore, liver disease has become increasingly relevant in primary care practice. Of the different types of liver disease, non-alcoholic fatty liver disease (NAFLD) is the most common (see Table 1, below) and although it mostly runs a benign course, it is a precursor to cirrhosis in some patients.

Table 1: UK incidence and relevance of different stages of liver disease
StageIncidenceRelevance
NAFLD 20–30% population2 Benign in most cases, but a precursor to cirrhosis for those progressing from NAFLD, through NASH, to fibrosis
NASH (hepatic inflammation due to NAFLD) 2–3% population2 Reversible with lifestyle change
Alcohol-related liver disease In 2014 alcohol caused 1.4% of all deaths, 63% of which resulted from alcoholic liver disease3 For people with alcoholic cirrhosis who continue to drink, 5-year survival rates are less than 50%4
Cirrhosis 10–20% of people with one of the three most common chronic liver diseases (NAFLD, alcohol-related liver disease, and chronic viral hepatitis) develop cirrhosis over a period of 10–20 years5 Irreversible. Around 600 people receive a liver transplant each year in the UK6
HCC 3–4% of people with cirrhosis develop HCC5 Without surveillance, outcome is typically poor (months) due to low chance of complete resection.
NAFLD=non-alcoholic fatty liver disease; NASH=non-alcoholic steatohepatitis; HCC=hepatocellular carcinoma

Liver toxicity—regardless of its origin—causes inflammation, which gradually leads to fibrosis, the precursor to irreversible cirrhosis. The liver disease progression pathway in Figure 1 (see below) shows mechanisms whereby different risk factors result in progressive liver disease ultimately leading to liver failure as well as increased risk of hepatocellular carcinoma. The majority of patients with NAFLD will run a benign course: identifying those at risk of disease progression is a vital step to ensure targeted intervention and appropriate follow up. NB For terms used in this article see Box 1 (below).

Figure 1: Algorithm showing the liver disease progression pathway2,5
Algorithm showing the liver disease progression pathway

* Further risk factors for cirrhosis include certain medications (methotrexate, amiodarone, sodium valproate, griseofulvin); inherited liver disease such as haemochromatosis; autoimmune liver disease.

HBV=hepatitis B virus; HCV=hepatitis C virus; NAFLD=non-alcoholic fatty liver disease; ARLD=alcohol-related liver disease; NASH=non-alcoholic steatohepatitis; ASH= alcoholic steatohepatitis

Algorithm developed by the authors, based on NICE Guideline 49 and NICE Guideline 50

Box 1: Terms used in this article

  • ARFI: acoustic radiation force impulse imaging (similar to TE, see below)
  • ARPI: aspartate transaminase (AST) to platelet ratio index. Used to predict cirrhosis if ELF is not available
  • Child-Pugh: a point-based score of the degree of cirrhosis (see Box 4, below)
  • ELF: enhanced liver fibrosis test (if available at your local lab)
  • MELD: model for end-stage liver disease. A numerical score used to assess the need for liver transplantation in people with cirrhosis (see Box 3, below)
  • TE: transient elastography. Used to measure liver stiffness as an indicator for cirrhosis/fibrosed tissue.

NICE guidelines on liver disease

NICE Guideline (NG) 49 on Non-alcoholic fatty liver disease (NAFLD): assessment and management2 and NG50 on Cirrhosis in over 16s: assessment and management5 were published in July 2016. These guidelines can help GPs to manage risk factors for liver disease more efficiently, by enabling them to differentiate between patients whose disease is likely to follow a relatively benign path, and patients who need closer monitoring or referral. Further information on other causes of cirrhosis that are not covered in this article, such as viral hepatitis, can be found in NICE Clinical Knowledge Summaries:

Non-alcoholic fatty liver disease

Assessing NAFLD in primary care

Primary care is best placed for early identification of people at risk of developing liver disease. A stepped approach can be useful for diagnosing and managing liver disease (see Figure 2, below).

Figure 2: Stepwise approach for diagnosing liver disease in primary care2,5
Stepwise approach for diagnosing liver disease in primary care

NAFLD=non-alcoholic fatty liver disease; LFTs=liver function tests; ELF=enhanced liver fibrosis; NASH=non-alcoholic steatohepatitis; TE=transient elastography; ARFI=acoustic radiation force impulse imaging

Algorithm developed by the authors, based on NICE Guideline 49 and NICE Guideline 50

Step 1: identifying NAFLD

Non-alcoholic fatty liver disease is more common in people with type 2 diabetes or metabolic syndrome (the clustering of insulin resistance, dyslipidaemia, central obesity, and hypertension); NAFLD can be considered as the liver's expression of the metabolic syndrome.9 Routine liver blood tests are not useful in diagnosing NAFLD or cirrhosis, as test results may be normal or raised at any stage of liver disease, even with advanced liver damage. There is insufficient evidence to recommend screening for NAFLD in high-risk groups.

Diagnosis of NAFLD in adults usually arises from incidental findings of fatty liver on ultrasound scan performed for other indications, or during investigation of abnormal liver function tests followed by clinical history to exclude other causes of fatty liver, such as harmful alcohol intake, hepatitis C, or certain drugs. It is therefore important to include consideration of NAFLD during chronic disease monitoring of other conditions.

In individuals at high risk of developing NAFLD, Bedogni et al suggest that the Fatty Liver Index (FLI) can be used to estimate risk of NAFLD as an alternative test to ultrasound.10An online version is available.

NICE NG49 recommends that liver ultrasound should be offered to children and young people with type 2 diabetes or metabolic syndrome who do not misuse alcohol. [NB NG49 defines children, young people and adults as follows: children—over 1 year to under 16 years; young people—16 years to under 18 years; adults—18 years or older.] If the results are normal, retesting with liver ultrasound should occur every 3 years. The emerging epidemic of childhood obesity means that increasing numbers of young people have NAFLD, with some prevalence studies showing up to 38% of obese children having evidence of NAFLD.2 This indicates a likelihood that significant liver disease may develop at earlier ages in future generations.1

Step 2: assessing those with NAFLD for advanced fibrosis

NICE NG49 recommends that testing for advanced liver fibrosis should be offered to people with NAFLD; consider using the enhanced liver fibrosis (ELF) blood test, which assesses three serum biomarkers shown to correlate with liver fibrosis. Patients with an ELF score of 10.51 or above should be diagnosed with advanced liver fibrosis and referred to a relevant specialist in hepatology.

Reassure adults and children or young people with an ELF score under 10.51 that they are unlikely to have advanced fibrosis, and offer retesting every 3 years for adults but every 2 years if the patient is under 18 years. No interim tests are needed.

NB ELF is not yet available in every locality but the recommendation in NICE NG49 to use ELF should result in it becoming more widely available. If ELF is not yet commissioned locally, alternative algorithm methods (not included in NICE NG49) for assessing advanced fibrosis may include the aspartate transaminase (AST) to platelet ratio index (APRI). An APRI calculator is available. NICE NG50 recommends that transient elastography (TE) or acoustic radiation force impulse imaging (ARFI) (whichever is available) should be offered to patients with NAFLD who have been diagnosed with advanced fibrosis by an ELF test.5

Management options for NAFLD

It is important to remember that NAFLD alone is a risk factor for type 2 diabetes, hypertension, and chronic kidney disease.2 In addition, for people with type 2 diabetes, NAFLD is a risk factor for atrial fibrillation, myocardial infarction, ischaemic stroke, and death from cardiovascular causes.2

There are no medical treatments for NAFLD but lifestyle improvements to increase physical activity and lower body mass index (BMI) can reduce liver fat content and influence outcomes. Practitioners should remind people to stay within the national recommended limits for alcohol consumption.2 Evidence does not currently support recommending abstinence from alcohol for people with NAFLD.

NICE NG49 recommends that people with NAFLD who are taking statins should keep taking them, because of the link between NAFLD and metabolic syndrome. Stopping statins should only be considered if liver enzyme levels double within 3 months of starting statins, including in people with abnormal baseline liver blood results.2

The limited pharmacological recommendations made by NICE NG49 apply only to secondary or tertiary care settings and are not covered in this article.

Cirrhosis

Diagnosing cirrhosis

Risk factors for cirrhosis are broader than for NAFLD and include hepatitis B and C virus infection, misuse of alcohol, obesity, and type 2 diabetes (separate NICE guidelines on these disorders are available on the NICE website.

Cirrhosis can be diagnosed by assessing liver 'stiffness' using TE or ARFI.5 Both TE and ARFI assess stiffness by measuring the propagation of a sheer wave through living tissue using ultrasound; as Young's modulus states, the more solid an object, the faster a wave will pass through it. Normal liver tissue is softer than fibrosed or cirrhotic liver, so the lower the result (measured in kilopascals), the less scarring has occurred. Together, TE and ARFI have significantly reduced the clinical reliance on liver biopsy.

Liver function tests (LFTs) are not useful in ruling out cirrhosis as results may appear normal due to any limited remaining normal liver tissue. The type of testing that should be offered varies between different risk groups (see Table 2, below).

Table 2: Cirrhosis testing for different risk groups5
Risk groupTest
  • People with hepatitis C infection
  • Men who consume over 50 units of alcohol per week and have done so for several months
  • Women who consume over 35 units of alcohol per week and have done so for several months
  • People diagnosed with alcohol-related liver disease
TE
  • People with NAFLD and advanced liver fibrosis as shown by ELF score above 10.51 (or raised APRI)
TE or ARFI
  • For people with hepatitis B virus
See NICE CG16511 section 1.3 on 'Assessment of liver disease in secondary specialist care—adults with chronic hepatitis B'.
TE=transient elastography; NAFLD=non-alcoholic fatty liver disease; ELF=enhanced liver fibrosis; ARFI=acoustic radiation force impulse imaging; ARPI=aspartate transaminase to platelet ratio index; CG=Clinical Guideline

NICE NG50 recommends that repeat testing for cirrhosis every 2 years should be offered to people with alcohol-related liver disease, people with hepatitis C virus who have not responded to antiviral therapy, and people with NAFLD and advanced liver fibrosis. There is no need to keep repeating an abnormal liver function test if a cause has been identified.5

Monitoring cirrhosis

People with cirrhosis should be monitored to assess their risk of developing complications (see Box 2, below); those who have, or are at high risk of, complications of cirrhosis should be referred to a specialist hepatology centre.5 Specialists use the model for end-stage liver disease (MELD) score (see Box 3, below)—and the Child-Pugh score (see Box 4, below)—to evaluate people with compensated cirrhosis and to assess need for, and prognosis of, liver transplantation. The MELD formula uses creatinine, bilirubin, international normalised ratio (INR), sodium, and recent dialysis history to estimate relative disease severity and likely survival of patients awaiting liver transplantation.13 A MELD score of 12 points or more indicates high risk of complications of cirrhosis.

Box 2: Symptoms and complications of cirrhosis12

Symptoms of compensated cirrhosis (symptoms may not appear until liver damage is extensive):

  • confusion, drowsiness, and slurred speech
  • easy bruising or bleeding (due to reduced clotting factor production)
  • fatigue
  • fluid retention—abdominal or peripheral
  • haematemesis or melaena
  • itching
  • jaundice
  • loss of appetite
  • palmar erythema
  • spider naevi
  • testicular atrophy and/or breast enlargement in men
  • weakness.

Complications of decompensated cirrhosis:

  • ascites
  • bleeding from oesophageal varices
  • hepatic encephalopathy
  • hepatocellular carcinoma
  • hepatopulmonary syndrome (triad of liver disease, intrapulmonary vascular dilatation, and arterial hypoxaemia)
  • hepatorenal syndrome (acute kidney injury due to severe liver disease)
  • hypersplenism
  • malnutrition
  • oedema
  • portal hypertension
  • spontaneous bacterial peritonitis.

Box 3: Model for end-stage liver disease13

View calculator.

MELD = 3.78 × ln[serum bilirubin (mg/dl)] + 11.20 × ln[INR] + 9.57 × ln[serum creatinine (mg/dl)] + 6.43

MELD score3-month mortality (%)14
<9 1.9
10–19 6.0
20–29 19.6
30–39 52.6
≥ 40 71.3

MELD=model for end-stage liver disease; INR=international normalised ratio


Box 4: Child-Pugh score15

View calculator.

Factor1 point2 point3 point
Bilirubin (mg/dl) <2 2-3 >3
Serum albumin (g/l) >35 28-35 <28
PT INR <1.7 1.7-2.2 >2.2
Ascites Absent Slight Moderate
Hepatic encephalopathy None Grade 1–2 Grade 3–4

Child-Pugh scoreChild-Pugh class1-year mortality (%)
5–6 A 016
7–9 B 19
10–15 C 55

PT=prothrombin time; INR=international normalised ratio

Oesophageal varices

After diagnosis of cirrhosis, upper gastrointestinal (GI) endoscopy to detect oesophageal varices should be offered and, if these are absent, ongoing surveillance offered every 3 years.5 Where varices are found, they may be treated with variceal band ligation to reduce the likelihood of catastrophic bleeding.

Antibiotic prophylaxis may be recommended by the hepatology team for people with upper gastrointestinal bleeding as secondary infection has been shown to worsen the prognosis.

Ascites

NICE NG50 recommends that prophylactic antibiotics (ciprofloxacin or norfloxacin) should be offered to people with cirrhosis until the ascites has resolved,5 to reduce the incidence of spontaneous bacterial peritonitis. NB At the time of publication (November 2016), neither ciprofloxacin nor norfloxacin had a UK marketing authorisation for this indication. The prescriber should follow relevant professional guidance, taking full responsibility for the decision. Informed consent should be obtained and documented. See the General Medical Council's Good practice in prescribing medicines—guidance for doctors for further information.17

Transjugular intrahepatic portosystemic shunt (TIPS) should be considered for people with cirrhosis who have refractory ascites.6 This is a procedure where, under radiological guidance, a communication is created between the portal vein and a hepatic vein in order to reduce portal hypertension, which would otherwise lead to oesophageal and gastric varices and ascites.

Hepatocellular carcinoma

NICE NG50 recommends that ultrasound should be offered every 6 months for people with cirrhosis who do not have hepatitis B infection [see NICE CG165 on Hepatitis B (chronic): diagnosis and management if cirrhosis is due to hepatitis B11] as surveillance for hepatocellular carcinoma (HCC).5 Interval cancers may develop; however, 6-monthly surveillance with ultrasound (with or without alpha-fetoprotein) has been shown to be cost effective.5 Early diagnosis of HCC means that it is much more likely to be treatable with resection, embolisation, or liver transplant.

Summary

Increasing trends in obesity, type 2 diabetes, and alcohol consumption have led to significant increases in morbidity and mortality from advanced liver disease in recent years. The high population prevalence of NAFLD—but its benign tendency in the majority of cases—means that evaluation should focus on people whose disease is at highest risk of progressing towards fibrosis (cirrhosis) of the liver.

New non-invasive blood tests and imaging techniques that assess risk of fibrosis and degree of liver stiffness have now reduced the reliance on liver biopsy to diagnose advanced liver disease. Commissioners are encouraged to invest in these tests to improve the efficiency of liver investigations in primary care as well as to reduce the current tendency for liver disease to present late at the stage where there are complications. Lifestyle change to address harmful alcohol intake, reduce high BMI, and increase physical activity will benefit people with all stages of liver disease.

Key points

  • LFTs are not useful in assessing the presence or relevance of NAFLD, risk of fibrosis, or in diagnosing cirrhosis, as results of these tests may be normal or raised throughout the spectrum of liver disease
  • It is important to be vigilant for cirrhosis in any patient with risk factors
  • Commissioners should ensure that ELF, and TE or ARFI, are available in their locality
  • Practitioners should:
    • refer any patient with a diagnosis of cirrhosis to a liver specialist for initial assessment
    • ensure that they have a practice lead for liver disease and use Read coding to maintain a list of patients diagnosed with, and at risk of, liver disease.

LFTs=liver function tests; NAFLD=non-alcoholic fatty liver disease; ELF=enhanced liver fibrosis; TE=transient elastography; ARFI=acoustic radiation force impulse imaging

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GP commissioning messages

written by Dr David Jenner, GP, Cullompton, Devon

  • Liver disease is a rising cause of morbidity and mortality, and is often associated with excess alcohol consumption and obesity
  • Public health professionals should identify risk factors for liver disease and introduce appropriate preventive measures in local health and wellbeing plans, coordinating their interventions with NHS commissioners
  • Commissioners should:
    • agree local diagnostic and referral pathways based on NICE NG49 and NICE NG50 to ensure the correct identification of people with liver disease who are at greatest risk of complications:
      • the pathway could include the diagnostic blood tests and algorithms cited in the article, to allow identification of high-risk patients for referral, and surveillance of low-risk patients in primary care
    • ensure the local availability of the ELF blood test: this is likely to prove cost effective over time through avoiding unnecessary referrals and reducing morbidity in people at high risk of cirrhosis.

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For more recommendations on the management of liver disease and cirrhosis, read the Guidelines summaries of NG49 on Non-alcoholic fatty liver disease (NAFLD): assessment and management and NG50 on Cirrhosis in over 16s: assessment and management

 

References

  1. Williams R, Aspinall R, Bellis M et al. Addressing liver disease in the UK: a blueprint for attaining excellence in health care and reducing premature mortality from lifestyle issues of excess consumption of alcohol, obesity, and viral hepatitis. Lancet 2014: 384 (9958): 1953–1997.
  2. NICE. Non-alcoholic fatty liver disease (NAFLD): assessment and management. NICE Guideline 49. NICE, 2016. Available at: www.nice.org.uk/ng49
  3. Office for National Statistics. Liver disease biggest cause of alcohol-related deaths in England and Wales. ONS, 2014. Available at:webarchive.nationalarchives.gov.uk/20160105160709/http://www.ons.gov.uk/ons/rel/subnational-health4/alcohol-related-deaths-in-the-united-kingdom/2012/sty-alcohol-releated-deaths.html (accessed 9 November 2016).
  4. NHS Choices. Alcohol-related liver disease. Available at: www.nhs.uk/Conditions/Liver_disease_(alcoholic)/Pages/Introduction.aspx (accessed 5 October 2016).
  5. NICE. Cirrhosis in over 16s: assessment and management. NICE Guideline 50. NICE, 2016. Available at: www.nice.org.uk/ng50
  6. NHS organ donation and transplantation. Annual report on liver transplantation—report for 2013/14 (1 April 2004–31 March 2014). Available at: www.odt.nhs.uk/pdf/organ_specific_report_liver_2014.pdf
  7. NICE. Clinical Knowledge Summaries. Hepatitis B. NICE, 2014. Available at: cks.nice.org.uk/hepatitis-b
  8. NICE. Clinical Knowledge Summaries. Hepatitis C. NICE, 2016. Available at: cks.nice.org.uk/hepatitis-c
  9. Almeda-Valdés P, Cuevas-Ramos D, Aguilar-Salinas C. Metabolic syndrome and non-alcoholic fatty liver disease. Ann Hepatol 2009; 8 (suppl 1): S18–24.
  10. Bedogni G, Bellentani S, Miglioli L et al. The Fatty Liver Index: a simple and accurate predictor of hepatic steatosis in the general population. BMC Gastroenterology 2006; 6: 33.
  11. NICE. Hepatitis B (chronic): diagnosis and management. Clinical Guideline 165. NICE, 2013. Available at: www.nice.org.uk/cg165
  12. Franciscus A. HCSP fact sheet. Symptoms and complications of cirrhosis. Available at: hcvadvocate.org/hepatitis/factsheets_pdf/Cirrhosis_Signs_and_Symptoms.pdf
  13. Kamath P, Wiesner R, Malinchoc M, et al. A model to predict survival in end-stage liver disease. Hepatology 2001: 33 (2): 464–470.
  14. Wiesner R, Edwards E, Freeman R et al. Model for end-stage liver disease (MELD) and allocation of donor livers. Gastroenterology 2003: 124 (1): 91–96.
  15. Pugh R, Murray-Lyon I, Dawson J et al. Transection of the oesophagus for bleeding oesophageal varices. Br J Surg 1973; 60: 646–649.
  16. Cholongitas E, Papatheodoridis G, Vangeli M et al. Systematic review: the model for endstage liver disease—should it replace ChildPugh’s classification for assessing prognosis in cirrhosis? Aliment Pharmacol Ther 2005; 22 (11–12): 1079–1089.
  17. General Medical Council. Good practice in prescribing and managing medicines and devices. GMC, 2013. Available at: www.gmc-uk.org/Prescribing_guidance.pdf_59055247.pdfG