Dr Jez Thompson offers seven top tips on dealing with the challenges involved in the diagnosis and management of non-alcoholic fatty liver disease in primary care

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Dr Jez Thompson

  • the causes and disease spectrum of non-alcoholic fatty liver disease (NAFLD)
  • risk factors for NAFLD, and diagnosis of the condition
  • lifestyle and other interventions delivered by primary care, and when to refer.

Read this article online at: GinP.co.uk/456836.article

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Primary non-alcoholic fatty liver disease (NAFLD) is characterised by excessive fat deposition in the liver that is not secondary to another source of liver damage,1,2 such as excessive alcohol use, chronic viral hepatitis, or some inherited and endocrine conditions.3,4 NAFLD is increasingly prevalent, particularly in developed countries,5 and is now estimated to affect 20–30% of the general population.2

NAFLD ranges in clinical severity from uncomplicated fatty liver (steatosis) to cirrhosis,1,2 which has the attendant risks of hepatocellular carcinoma (HCC) and decompensated liver disease.6,7 Patients with NAFLD are usually asymptomatic,8 although the rate of disease progression varies depending on the presence of risk factors,2 which include obesity and type 2 diabetes.2,3

There are important opportunities for early diagnosis and risk factor management in primary care, with the twin goals of reversal of fatty infiltration through dietary and lifestyle changes, and monitoring patients for the development of cirrhosis and its complications.

1. Recognise those patients at high risk of developing NAFLD

The underlying cause of NAFLD, the pathological mechanisms of NAFLD progression, and the reasons why this progression occurs in some people but not others, are not fully understood.

Most factors that contribute to NAFLD risk are environmental. Risk factors for the development of NAFLD are shown in Box 1.3  

Box 1: Risk factors for NAFLD3

  • Metabolic risk factors for non-alcoholic fatty liver disease (NAFLD) include features of metabolic syndrome that indicate increased cardiovascular risk:
    • central obesity—91% of people with body mass index (BMI) >30 kg/m2 or an increased waist circumference (>94 cm in men or >80 cm in women [in White people]) have been found to have NAFLD[A]
    • impaired glucose regulation or type 2 diabetes mellitus (T2DM)—the global prevalence of NAFLD among people with T2DM is 55%[B]
    • hypertension[C]
    • hyperlipidaemia (hypertriglyceridaemia and/or low level of high-density lipoprotein [HDL]-cholesterol)[D]
  • Other possible risk factors for NAFLD include:
    • obstructive sleep apnoea syndrome[E]
    • endocrine disorders—e.g. polycystic ovary syndrome,[F] hypothyroidism,[G] and growth hormone deficiency
    • a family history of NAFLD
    • ethnicity—higher risk in Hispanic and Asian people, lower risk in Black people
    • nutritional—total parenteral nutrition (TPN) and refeeding syndrome, rapid weight loss, and jejunoileal bypass surgery
    • drugs—e.g. nonsteroidal anti-inflammatory drugs, amiodarone, corticosteroids, diltiazem, methotrexate, and tamoxifen
    • other liver conditions, such as hepatitis C[H] and Wilson’s disease.

[A] See the NICE Clinical Knowledge Summary on obesity for more information: cks.nice.org.uk/topics/obesity/
[B] See the NICE Clinical Knowledge Summary on type 2 diabetes for more information: cks.nice.org.uk/topics/diabetes-type-2/
[C] See the NICE Clinical Knowledge Summary on hypertension for more information: cks.nice.org.uk/topics/hypertension/
[D] See the NICE Clinical Knowledge Summary on lipid modification—CVD prevention for more information: cks.nice.org.uk/topics/lipid-modification-cvd-prevention/
[E] See the NICE Clinical Knowledge Summary on obstructive sleep apnoea syndrome for more information: cks.nice.org.uk/topics/obstructive-sleep-apnoea-syndrome/
[F] See the NICE Clinical Knowledge Summary on polycystic ovary syndrome for more information: cks.nice.org.uk/topics/polycystic-ovary-syndrome/
[G] See the NICE Clinical Knowledge Summary on hypothyroidism for more information: cks.nice.org.uk/topics/hypothyroidism/
[H] See the NICE Clinical Knowledge Summary on hepatitis C for more information: cks.nice.org.uk/topics/hepatitis-c/

NAFLD=non-alcoholic fatty liver disease; CVD=cardiovascular disease

© 2021. Non-alcoholic fatty liver disease (NAFLD): risk factors. NICE Clinical Knowledge Summary. Available at: cks.nice.org.uk/topics/non-alcoholic-fatty-liver-disease-nafld/background-information/risk-factors/

All rights reserved. Subject to Notice of rights. NICE guidance is prepared for the National Health Service in England. All NICE guidance is subject to regular review and may be updated or withdrawn. NICE accepts no responsibility for the use of its content in this product/publication. See www.nice.org.uk/re-using-our-content/uk-open-content-licence for further details.

Extremes of body weight

It is estimated that NAFLD is present in 80–90% of people classed as obese.9 However, it is important to remember that not everyone who is overweight develops fatty liver, and not everyone who has fatty liver is overweight. NAFLD is also associated with the metabolic changes that occur during rapid weight loss and starvation, such as in anorexia nervosa.10

Genetic predisposition

Genetic factors may explain why some individuals are predisposed to fat deposition in the liver, and why hepatic steatosis develops into more serious liver disease in certain patients. Studies have identified specific genes—including variants of PNPLA3, TM6SF2, and HSD17B13— that are associated with progression to severe disease, including cirrhosis and HCC, in people with NAFLD.11 Genetic predisposition is thought to underlie 27–39% of cases of NAFLD.12

2. Understand how to diagnose NAFLD in adults

Diagnosing NAFLD in adults can be difficult. Challenges include:

  • the high prevalence of risk factors
  • the benign clinical course of NAFLD in most patients
  • a lack of good-quality evidence for factors that can predict disease progression
  • the absence of a simple, cost-effective, sensitive, and specific screening test.

NICE Guideline (NG) 49, Non-alcoholic fatty liver disease (NAFLD): assessment and management, does not make any recommendations on the screening of asymptomatic adults with risk factors for NAFLD.2 Therefore, whether to investigate patients with multiple and severe risk factors for NAFLD remains an individual clinical decision. The Fatty Liver Index13 is one example of a simple algorithm-based assessment that brings together clinical examination findings—such as body mass index (BMI), waist measurement, and standard blood test results—to give an estimate of the risk of NAFLD.13 Some clinicians may find this approach useful; however, NICE found that these tests had limitations, and was unable to recommend their use.14

Pragmatically, NAFLD can be suspected in primary care in two circumstances. Firstly, fatty changes in the liver are a fairly common incidental finding on upper abdominal ultrasound; and secondly, the onward investigation of patients with persistently abnormal liver function test (LFT) results may point to a diagnosis of NAFLD. However, it should be noted that patients on any part of the NAFLD disease spectrum may have normal LFTs, and that a routine, standard LFT panel has no value in excluding NAFLD15 —in fact NICE does not recommend that routine liver blood tests be used to rule out NAFLD.2

A useful algorithm detailing the initial response to abnormal liver blood tests is shown in Figure 1.16

BSG NAFLD Figure 1

Figure 1: British Society of Gastroenterology algorithm outlining the response to abnormal liver blood tests16

This figure details the initial response to abnormal liver blood tests. Boxes in yellow indicate the initial evaluation of the clinical presentation. Patients with marked derangement of liver blood tests, synthetic failure and/or suspicious clinical symptoms/signs should be considered for urgent referral to secondary care (red box). For the remainder, a clinical history alongside evaluation of the pattern of liver blood test derangement will determine choice of pathway and is shown in the grey boxes. A grey box indicates all of the tests that should be requested at that stage rather than a hierarchy within it. The presence of metabolic syndrome criteria should be sought to support a diagnosis of NAFLD. For children, the guideline should be consulted for modification of recommendation. Areas of diagnostic uncertainty are indicated in orange boxes and the decision for repeat testing or referral to secondary care will be influenced by the magnitude of enzyme elevation and clinical context. Green boxes indicate final/definitive outcomes for users of the pathway. Abnormal USS may include extrahepatic biliary obstruction due to malignancy, which should result in urgent referral.

BMI=body mass index; ARLD=alcohol-related liver disease; ALT=alanine aminotransferase; AST=aspartate aminotransferase; INR=international normalised ratio; ALP=alkaline phosphatase; GGT=gamma-glutamyltransferase; FBC=full blood count; HbA1c =glycated haemoglobin; LDH=lactate dehydrogenase; NAFLD=non-alcoholic fatty liver disease; USS=ultrasound scan

Newsome P, Cramb R, Davison S et al. Guidelines on the management of abnormal liver blood tests. Gut  2018; 67  (1): 6–19. Reproduced under the terms of the CC BY 4.0 licence.

NAFLD is a clinical and pathological diagnosis that requires the exclusion of other primary causes of liver disease. When NAFLD is suspected, it is important to ask about alcohol consumption to rule out alcohol-related liver disease as the underlying cause of fatty changes;2 a threshold for alcohol consumption of less than 20 g/day (2.5 units/day) for women and less than 30 g/day (3.75 units/day) for men has been adopted to exclude alcohol-related steatosis.17 Fatty liver changes are part of the pathological process of many liver diseases, and chronic viral hepatitis, drug-induced liver disease, haemochromatosis, Wilson’s disease, and autoimmune liver disease must all be excluded before NAFLD can be diagnosed.17 A standard panel of relevant blood tests is available in many areas, and is often termed a ‘secondary liver screen’, ‘liver aetiology screen’, or something similar, depending on the area. 

3. Be aware of the natural history and disease spectrum of NAFLD

NAFLD represents a spectrum of liver disease ranging from simple, benign fatty deposition to end-stage decompensated cirrhosis. The four main stages of NAFLD are described in the following sections.

Hepatic steatosis

Hepatic steatosis, or simple fatty liver, is defined as abnormal fat deposition within liver cells.18 At this stage, there has not been a progression to inflammation or scarring.14 For most people, this fatty infiltration is harmless and asymptomatic.18 However, for some, it can result in the development of local inflammation and progression to more serious disease—the risk of developing cirrhosis is 4.7 times higher in patients with NAFLD than in the general population,19 but disease progression is typically slow.20 Although the risk of progression to cirrhosis in NAFLD is lower than that in some other liver conditions, the high prevalence of NAFLD means it is an increasingly important cause of advanced liver disease.

Non-alcohol-related steatohepatitis

Some patients with fatty liver develop non-alcohol-related steatohepatitis (NASH), a more aggressive condition characterised by liver inflammation.18 The prevalence of NASH in the general population is thought to be around 2–3%,2 and the condition may progress to cirrhosis over time.20

Fibrosis

Persistent inflammation of the liver in NASH may lead to fibrotic changes, such as scarring around the liver and nearby blood vessels.18 In early fibrosis, liver function is preserved,18 as liver cell death may be minimal and liver architecture is maintained.

Cirrhosis

Cirrhosis is a life-threatening, irreversible condition in which long-term inflammation has resulted in the liver shrinking and becoming scarred and lumpy,18 with extensive fibrosis surrounding nodules of regenerating liver tissue.6 Both the structure and function of the liver are significantly disrupted in cirrhosis.6 Cirrhosis is the most severe expression of NAFLD, and is associated with decompensated liver failure, portal hypertension, and HCC.6,7,18

4. Establish disease severity in adults diagnosed with NAFLD

Once NAFLD has been diagnosed, the next steps in the clinical assessment are to evaluate disease severity and to establish whether fibrosis is present. The British Society of Gastroenterology (BSG) guidelines on the management of abnormal liver blood tests contain a helpful algorithm to determine the likelihood of fibrosis (see Figure 2).16

BSG NAFLD Figure 2_v2

Figure 2: British Society of Gastroenterology non-alcoholic fatty liver fibrosis algorithm16

For those patients with NAFLD or liver disease of unknown aetiology, the next step is to determine the likelihood of liver fibrosis. Initial assessment includes calculation of a FIB-4 Score or NFS with values <1.30 and ≤-1.455, respectively, signifying a low risk of advanced fibrosis.

[A] Higher cut-off points of <2.00 (FIB-4) and <0.120 (NFS) should be used for patients aged ≥65 years.

Second-line tests that should be considered include serum markers such as the ELF™ Test and imaging modalities such as ARFI elastography/FibroScan®. For children, the guideline should be consulted for modification of recommendation. Cut-off points for ARFI vary according to manufacturer and thus should be tailored to the device used.

NAFLD=non-alcoholic fatty liver disease; FIB-4=Fibrosis 4; NFS=NAFLD Fibrosis Score; ELF=Enhanced Liver Fibrosis; ARFI=acoustic radiation force impulse; HCC=hepatocellular carcinoma

Newsome P, Cramb R, Davison S et al. Guidelines on the management of abnormal liver blood tests. Gut 2018; 67 (1): 6–19. Reproduced under the terms of the CC BY 4.0 licence.

NG49 recommends using the Enhanced Liver Fibrosis (ELF™) Test14,21 to identify advanced liver fibrosis in patients diagnosed with NAFLD.2 The ELF Test is a proprietary blood test that combines a panel of three serum biomarkers—tissue inhibitor of matrix metalloproteinase 1, procollagen III amino-terminal peptide, and hyaluronic acid—to produce an ‘ELF Score’.14,21 An ELF Score greater than 10.51 is associated with the presence of fibrosis in individuals with NAFLD.2,14

However, the ELF Test may not be available in all areas. Alternative assessments of fibrosis include the Fibrosis 4 Score and the NAFLD Fibrosis Score, although these are not specifically recommended in NG49.17 These scoring systems use readily accessible patient data—such as age, BMI, and serum and other biomarkers—in simple algorithms to provide indirect estimates of fibrosis risk. Easy-to-use ‘calculators’ for these algorithms are readily available on the internet.22,23

In secondary care, liver biopsy remains the diagnostic gold standard in the assessment of liver fibrosis and cirrhosis, but the procedure is invasive and expensive.14,24 Although computed tomography can also be used to diagnose fatty liver, the imaging modality is a significant source of ionising radiation.14 Ultrasound scanning and magnetic resonance imaging (MRI) are alternative imaging techniques, but ultrasound findings can be normal in NAFLD; 30% steatosis is the accepted lower limit for reliable detection by ultrasound.14

5. Consider delivery of lifestyle and other interventions in primary care

Because of the risk factors and comorbidities associated with NAFLD, a high proportion of patients with NAFLD will already attend primary care services for regular monitoring and treatment of long-term conditions such as diabetes, obesity, and hypertension, and there is considerable overlap between the management of these conditions and the management of NAFLD.

Lifestyle changes

Lifestyle changes are likely to be beneficial for all patients with or at risk of developing NAFLD by helping to reduce liver fat content and lower the risk of disease progression.25 NG49 recommends that people with NAFLD should be given advice about the following lifestyle modifications,2 which aim to reduce the risk of morbidity and mortality related to NAFLD and its comorbidities.25

Physical activity

NG49 states that there is some evidence that exercise can reduce liver fat content;2,14 providing patients who have NAFLD with guidance on increasing their level of physical activity, such as that provided by NICE,26,27 is therefore of value.

Diet and weight loss

Advice on diet and weight loss is appropriate for people with NAFLD who are overweight or obese,2,14 and is summarised in NICE Clinical Guideline 189, Obesity: identification, assessment and management.28 Weight reductions of 10% or greater can induce a near universal resolution of NASH and improvement of fibrosis by at least one stage.29

Bariatric surgery may be considered for patients who fit the referral criteria,28 and has been shown to reduce NAFLD pathogenesis in addition to improving metabolic parameters.30

Alcohol consumption

Alcohol use may be harmful to liver health in people who have NAFLD,31 and patients—particularly those with cirrhosis—should be encouraged to stay within national recommended limits.2,14

Screening

Obesity, dyslipidaemia, and type 2 diabetes are known risk factors for NAFLD;3 conversely, NAFLD is a risk factor for type 2 diabetes, hypertension, and chronic kidney disease and, in people with type 2 diabetes, the condition is a risk factor for atrial fibrillation, myocardial infarction, ischaemic stroke, and death from cardiovascular causes.2 Consideration should therefore be given to screening patients with NAFLD for other relevant conditions (see Box 2).

Patients with NAFLD should be screened for related conditions, including:

  • fibrosis—in adult patients with NAFLD without fibrosis (ELF Score <10.51), NICE recommends retesting for fibrosis on a 3-yearly basis2
  • advanced liver fibrosis
    • liver blood tests may show a raised bilirubin level, a high AST to ALT ratio, and a low level of albumin in advanced liver fibrosis17
    • a full blood count test may show unexplained low platelets, a sign of advanced liver fibrosis17
    • a clotting screen may show that blood clotting is deranged in advanced liver fibrosis17  
  • signs of advanced liver disease—screen for jaundice, spider naevi, palmar erythema, ascites, hepatomegaly, splenomegaly, and hepatic encephalopathy17
  • overweight and obesity—measure height and weight (to calculate BMI), and waist circumference17
  • high blood pressure17
  • impaired glucose regulation or type 2 diabetes—check HbA1c level17
  • hyperlipidaemia—check lipid profile17
  • chronic kidney disease—assess renal function17
  • hypothyroidism—there may be an association between hypothyroidism and NAFLD, and it may be useful to check thyroid function17
  • liver effects of commonly used medications—many patients diagnosed with NAFLD will be taking statins, and NICE advises that patients should keep taking them unless liver enzyme levels double within 3 months of starting statins, including in people with abnormal baseline liver blood results.2

NAFLD=non-alcoholic fatty liver disease; ELF=Enhanced Liver Fibrosis Test; AST=aspartate aminotransferase; ALT=alanine aminotransferase; BMI=body mass index; HbA1c=glycated haemoglobin 

6. Know when to refer an adult patient with NAFLD to specialist care

Although most advice on lifestyle changes and risk reduction measures for patients with NAFLD will be delivered in primary care, some patients will require referral to secondary or tertiary care. NICE recommends that adults with NAFLD diagnosed with advanced liver fibrosis (ELF Score greater than 10.51, or other score indicating fibrosis17) should be referred to a specialist in hepatology.2 If a diagnosis of cirrhosis is established, the patient will be followed up and monitored in secondary care.32

Referral is also covered in the British Society of Gastroenterology non-alcoholic fatty liver fibrosis algorithm (see Figure 2).16

7. Be familiar with pharmacological and other interventions for NAFLD

A number of medical treatments have been proposed for the management of NAFLD, including insulin-sensitising drugs, such as pioglitazone, and anti-inflammatory agents, such as vitamin E.14 Currently, neither pioglitazone nor vitamin E has a UK licence for use in NAFLD,2 but there is some supportive clinical evidence for the use of some agents.

NICE states that, in secondary or tertiary care settings, pioglitazone or vitamin E can be considered for adults with NAFLD and advanced liver fibrosis, irrespective of whether they have diabetes.2 In my opinion, it may be useful to consider the presence of NAFLD when choosing the most appropriate antidiabetic agent for type 2 diabetes in primary care, where pioglitazone may be considered.

Other approaches to the management of NAFLD have been investigated; however, NICE found no evidence to suggest that measures such as reduction in sucrose or fructose intake, omega-3 dietary supplements, or drinking caffeine in coffee protect against NAFLD progression.2,14 There may be some evidence to support the use of antioxidants such as anthocyanins in NAFLD,33 but these are not currently recommended by NICE.

Medical treatment may be considered for suitable patients with NAFLD to support weight loss after dietary, exercise, and behavioural approaches have been started and evaluated.28

Summary

The prevalence of NAFLD is increasing, and it has become one of the most important liver diseases worldwide. Targeted diagnosis, lifestyle modification advice, and management of comorbidities are necessary to improve the clinical outcome in patients with NAFLD.

Key points

  • Primary NAFLD is defined as excessive fat deposition in the liver that is not secondary to another source of liver damage
  • NAFLD represents a spectrum of liver disease ranging from simple, benign fatty deposition to end-stage decompensated cirrhosis
  • Most factors that contribute to NAFLD risk are environmental; risk factors include obesity, type 2 diabetes, and hyperlipidaemia
  • Diagnosing NAFLD requires the exclusion of other primary causes of liver disease, such as alcohol misuse, chronic viral hepatitis, drug-induced liver disease, haemochromatosis, Wilson’s disease, and autoimmune liver disease
  • After diagnosis, disease severity should be ascertained using the ELF Test
    • if unavailable, alternative scoring systems include the FIB-4 Score and NAFLD Fibrosis Score
  • Primary care plays a key role in the delivery of lifestyle and other interventions, such as physical activity and dietary changes
    • screening for related conditions, such as type 2 diabetes, chronic kidney disease, and cardiovascular disease, should also be conducted in primary care
  • Adults with NAFLD diagnosed with advanced liver fibrosis should be referred to a specialist in hepatology.

NAFLD=non-alcoholic fatty liver disease; LFT=liver function test; ELF=Enhanced Liver Fibrosis; FIB-4=Fibrosis 4

Useful resources

Note: At the time of publication (March 2022), some of the drugs discussed in this article did not have UK marketing authorisation for the indications discussed. Prescribers should refer to the individual summaries of product characteristics for further information and recommendations regarding the use of pharmacological therapies. For off-licence use of medicines, 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 and managing medicines and devices for further information.

Dr Jez Thompson

GP, Leeds

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Reflection is important for continuous learning and development, and a critical part of the revalidation process for healthcare professionals. Reflect on what you have learned after reading this article with our interactive template.

References

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