Liver disease is a global issue and is recognised as the fifth leading cause of death worldwide (Global Burden of Disease, 2020). Over the last 50 years, the UK has witnessed an exponential increase in liver disease mortality whereas death rates from other medical conditions such as cancer, heart and respiratory disease have fallen (British Society of Gastroenterology (BSG), 2009; Williams, 2015; Williams et al, 2018; British Liver Trust (BLT), 2019; Public Health England (PHE), 2020a).
Liver disease is the third most common cause of premature death in those under 65 years old (BSG, 2009; PHE, 2017; BLT, 2019; PHE, 2020a), with death rates in this cohort group increasing by over 400% since the 1970s (BLT, 2019), and is the second leading cause of death for people aged 35–49 years, accounting for 9.8% of deaths in that age group (Gov.uk, 2022). These findings are supported by data published in 2015 by PHE which additionally report that over 600 000 people in the UK have some form of serious liver disease with over 60 000 diagnosed with liver cirrhosis. Further statistics published in the Lancet Standing Commission on Liver Disease in the UK report (Williams et al, 2018), emphasised this stark reality and postulated that liver disease could overtake ischaemic heart disease with regards to years of working life lost. This fact was confirmed in England in 2020 by the government reporting that working lives lost by liver disease overtook ischaemic heart disease and accidental poisoning (Gov.uk, 2022).
Unfortunately, signs of liver disease are generally not apparent unless it has reached an advanced stage, evidenced by jaundice, ascites and oesophageal and gastric varices – all late signs of portal hypertension (Bacon et al, 2005; Oliver et al, 2022). This is supported by research from the NIHR Southampton Biomedical Research Centre (2020), who established that 75% of people with liver cirrhosis were not diagnosed in primary care but in a hospital setting, when the disease had already progressed and treatment options were limited. Therefore, liver disease is acknowledged as the ‘silent killer’ (BLT, 2021), which highlights the importance of early diagnosis and treatment.
There are many causes of chronic liver disease, but the top three are alcohol, viral hepatitis, and non-alcoholic fatty liver disease (NAFLD). This article will focus on NAFLD.
Non-alcoholic fatty liver disease
NAFLD is an umbrella term used to describe a build-up of fat in the liver, known as steatosis. Fatty liver is the first stage of liver disease, whatever the underlying aetiology may be. In the early stages, NAFLD does not cause harm and is reversible. However, most people are unaware that they have developed NAFLD, and as there are no obvious symptoms to report, this makes diagnosis difficult. If left untreated, steatosis can develop into the more serious form of non-alcoholic steatohepatitis (NASH), where the liver becomes inflamed, and over time this can further develop into fibrosis and cirrhosis (Table 1).
Table 1. The four stages of non-alcoholic fatty liver disease
| Stage | Descriptor | Definition |
|---|---|---|
| 1 | Simple fatty liver (steatosis) | Harmless build-up within liver cells that may only be diagnosed incidentally |
| 2 | Non-alcoholic steatohepatitis (NASH) | A more serious form of NAFL where the liver has become inflamed |
| 3 | Fibrosis | Persistent inflammation causes scar tissue in the liver, but the liver can still function normally |
| 4 | Cirrhosis | Occurs after years of inflammation. The liver is scarred, atrophies and can lead to end stage liver failure |
Adapted from: NHS (2022)
Prevalence
In the UK, the prevalence of simple steatosis/NAFLD is between 20 and 30% of the population, with a further 2–3% diagnosed with the more serious NASH (McPherson et al, 2022; NHS, 2022). Awareness of the increasing incidence of NASH was recognised in earlier publications by the National Institute of Health and Care Excellence (NICE, 2016) as well as the European Association for the Study of the Liver (EASL), European Association for the Study of Diabetes (EASD) and European Association for the Study of Obesity (EASO) clinical practice guidelines (EASL et al, 2016), with the acknowledgement that NASH was linked to the rise in rates of obesity and metabolic syndrome, which is a combination of chronic conditions that indicates increased cardiovascular risk. Metabolic syndrome includes central obesity, insulin resistance or type 2 diabetes, hypertension and dyslipidaemia (NICE, 2016).
NAFLD is not just an issue in the UK. In the USA, NAFLD is the most common cause of chronic liver disease (Ando and Jou, 2021) and is the second leading cause of liver transplantation (Wong et al, 2015). In a NAFLD consensus statement (Lazarus et al, 2022), NAFLD was purported to affect approximately a quarter of the global adult population, causing a substantial burden of ill health with wide-ranging social and economic implications. However, despite its prevalence, most patients and allied health professionals are unaware of the serious implications of being diagnosed with this condition.
Renaming the disease
An international consensus panel (Eslam et al, 2020a; 2020b) produced an important report advocating renaming the disease from NAFLD to metabolic (dysfunction) associated fatty liver disease (MAFLD). This change in terminology is purported to reflect the underlying cause more accurately, enabling the optimal management and treatment to be given. However, this renaming has not been without controversy.
An article published by Younossi et al (2021) recognised that the term NAFLD was suboptimal, as it underemphasised the main underlying aetiology of the condition, namely metabolic risk factors, but further stated that the new name of MAFLD was also ambiguous, recommending the creation of an international consensus group representing patient organisations, the bio-pharmaceutical industry, policy makers and the relevant scientific liver societies from across the globe.
Kang et al's (2021) review article concurred with the above findings, adding that the term NAFLD overemphasised the term alcohol, whereas metabolic issues being the primary cause of NAFLD was understated. However, they concluded that the new nomenclature's emphasis on metabolic dysfunction could mean that patients diagnosed with fatty liver, without the associated metabolic syndrome, would be excluded from MAFLD criteria and may even be missed from being given a diagnosis and appropriate follow-up, thus potentially being at risk of developing future disease. An earlier article by Huang et al (2020) agreed with these findings.
Regardless of the name, people diagnosed with NAFLD, when compared to the general population, have an increased risk of overall mortality. The most common causes of death are liver-related complications, malignancy and cardiovascular disease (McPherson et al, 2022). It is therefore important for health professionals to identify those at risk.
Significance of obesity
Obesity is associated with the development of NAFLD. A study by Portillo-Sanchez et al (2015) noted that over 90% of patients who underwent bariatric surgery were discovered to have NAFLD. These findings were confirmed by recent research into the UK Biobank data by De Vincentis et al (2022), who established that obesity is among the main determinants of NAFLD progression towards severe liver disease. Interestingly, they additionally noted that obesity along with age, waist circumference, type 2 diabetes and the PNPLA3 variant – a gene that provides instructions for making a protein called adiponutrin, found in fat cells (adipocytes) and liver cells (hepatocytes) – were also risk factors for developing liver disease, with a significant correlation between an increased waist circumference and the development of cirrhosis.
Having established that obesity contributes to the development of NAFLD, diabetes, heart disease and some cancers, it was disturbing to see published statistics from The King's Fund (2021) reporting that 64% of adults in England were overweight in 2019, with 28% in the obese category and 3% morbidly obese. The King's Fund (2021) report also highlighted that there were more than 1 million hospital admissions linked to obesity in 2019/20, which was an increase of 17% from the previous year. By 2050, the cost of treating obesity ill health is projected to be £9.7 billion. The increasing prevalence of obese adults and children correlates with the increase in cases of type 2 diabetes and metabolic syndrome, potentially leading to the development of NAFLD. This fact suggests there is a huge number of undiagnosed and untreated NAFLD cases.
Diagnosis
Any patient who falls in the obese category and/or has type 2 diabetes or insulin resistance and/or is diagnosed with metabolic syndrome should be tested for NAFLD. Nurses are often in the best positions to prompt early investigation. Diagnosis should not be made solely based on abnormal liver function tests (LFTs), as sometimes the results of these blood tests are not elevated. Fatty liver on ultrasound is determined by a hyperechogenic picture of the liver, demonstrated by a lighter, brighter looking liver (Mortimore and Mayes, 2019). The finding of liver steatosis on ultrasound, coupled with abnormal LFTs should prompt investigation of other causes, such as alcohol and blood-borne viruses. However, once a diagnosis of NAFLD is given, it should also trigger a risk assessment for liver fibrosis (McPherson et al, 2022). This risk assessment can be undertaken by simple blood tests and a scoring system, such as the FIB-4 scoring system.
If liver fibrosis is diagnosed, or there is uncertainty regarding diagnosis, for example an overlap of another underlying aetiology, or to evaluate the severity of NASH when non-invasive tests have been inconclusive, then a liver biopsy should be considered (McPherson et al, 2022). However, this is an invasive procedure which has known risks, including haemorrhage and mortality (Vali et al, 2020). If a liver biopsy is required then quality standards published by the British Association for the Study of the Liver (BASL) and British Society of Gastroenterology (BSG) NAFLD Special Interest Group (McPherson et al, 2022) state that all ‘liver biopsies should be processed, stained, and examined according to the UK Royal College of Pathologists guidelines and reported by pathologists who participate in the liver External Quality Assurance’. This ensures parity among histopathologists across the UK.
Transient elastography, also known as Fibroscan, is another modality that can be used to assess fibrosis (Pathik et al, 2015). If readings suggest fibrosis, this may prompt a decision to biopsy the liver for staging to assess the severity. If severe fibrosis/cirrhosis is diagnosed, then the patient will require 6-monthly hepatocellular carcinoma surveillance, in line with NICE (2016) cirrhosis guidance.
Scoring systems
The FIB-4 scoring system uses a combination of patient age, platelet count, aspartate transaminase (AST) levels and alanine aminotransferase (ALT) levels – part of LFT results. The scoring system creates a score. If the score is less than 1.45 it has a negative predictive value of over 90% for advanced liver fibrosis of multiple aetiologies. A negative predictive value means the likelihood that an individual with a negative test result is truly unaffected (Sterling et al, 2006; McPherson et al, 2010). On the other hand, a score of greater than 3.25 has a positive predictive value of 65% for advanced fibrosis with a specificity of 97%. This means that the proportion of patients truly diagnosed as positive is 65% (NICE, 2016; Hudson et al, 2017).
NICE (2016) recommend considering the use of the Enhanced Liver Fibrosis (ELF) test to assess the risk of advanced liver fibrosis in people with suspected NAFLD. The ELF test is an algorithm that requires the measurement of hyaluronic acid, amino-terminal propeptide of type III procollagen (PIIINP) and tissue inhibitor of metalloproteinase 1 (TIMP-1) (Buzzetti et al, 2015). This test has a high negative predictive value, but the positive predictive value is low (Vali et al, 2020). Additionally, NICE (2016) recommend using the NAFLD fibrosis score (NFS), which requires six variables to be entered, namely (Chalasani et al, 2012):
- Age
- Body mass index
- Platelet count
- ALT level
- AST level
- Blood glucose.
After these investigations, patients graded as high risk for advanced fibrosis or cirrhosis must be referred to a hepatologist in secondary care. For patients categorised as indeterminate risk, other tests can be offered such as transient elastography or the ELF test, but often require referral to secondary care for these tests to be undertaken. Low-risk patients can be managed in the community with a focus on lifestyle advice and cardiovascular risk reduction, although it is recommended that all patients with NAFLD should be assessed for fibrosis using non-invasive tests every 3 years (McPherson et al, 2022). In addition, patients with NAFLD should be screened annually for type 2 diabetes (using HbA1c), hypertension and dyslipidaemia.
Treatment
Health promotion in the form of lifestyle advice is the mainstay of treatment for NAFLD, with an emphasis on weight reduction and healthy diet (BSG, 2020). However, some medications can be prescribed to assist in the treatment of NAFLD/NASH. For those that have type 2 diabetes, insulin sensitisers are prescribed such as metformin or pioglitazone, as these medications allow cells to become more responsive to insulin. This responsiveness enables more glucose to be removed from the blood, thereby reducing sugar levels. However, NICE (2016) guidelines recommend caution if prescribing pioglitazone. It is contraindicated in people with a history of heart failure, previous or active bladder cancer and those under investigation for macroscopic haematuria, thus all patients should have a comprehensive history taken prior to commencement.
Vitamin E can be prescribed but usually for the treatment of NASH. Vitamin E is a fat-soluble antioxidant and is postulated to help protect cell membranes from reactive oxidative stress, a cause of inflammation (Perumpail et al, 2018), and therefore improve inflammation from NASH. In a systematic literature review by Perumpail et al (2018), the evaluated studies demonstrated an improvement in blood results and evidenced that in some patients their LFTs returned to normal limits. Moreover, on histological examination of liver samples, it was noted that those prescribed vitamin E had an improvement in liver inflammation and reduced levels of steatosis. However, it is worth noting that earlier studies linked high dose vitamin E supplementation with an increase in all-cause mortality (Brown and Crowley, 2005; Miller et al, 2005). Considering this, the NICE (2016) and EASL et al (2016) clinical practice guidelines for the management of NAFLD do make recommendations for the use of vitamin E, but advocate that vitamin E and pioglitazone should only be prescribed for adults with advanced liver fibrosis after considering the patient's comorbidities.
Lipid-lowering medications such as statins are sometimes prescribed in patients with dyslipidaemia. Statins lower cholesterol and other lipids, which may reduce the risk of heart and blood vessel disease.
Over the last 10 years, there has been increasing interest in the protective effects of caffeinated coffee. Drinking four cups or more per day has been shown to improve LFTs, reduce fibrosis and have protective effects against hepatocellular liver cancer (BLT, 2016; Heath et al, 2017; Ebadi et al, 2021).
The practice nurse role in health promotion
Practice nurses have a huge part to play in health promotion to all patients who are diagnosed with NAFLD/MAFLD. However, as previously discussed, there are potentially many people who are unaware that they have this condition and have not received a diagnosis. This emphasises why health promotion is extremely important in all patients who have a high body mass index, a diagnosis of type 2 diabetes, insulin resistance, hyperlipidaemia and/or metabolic syndrome, all of which are precursors for developing NAFLD/MAFLD.
Health promotion necessitates thorough history-taking to check patients’ current dietary and exercise habits. In addition, a detailed alcohol history using the AUDIT-C (Table 2) questionnaire as well as asking questions regarding illicit drug use and smoking history are important, all of which should be accurately documented.
Table 2. Alcohol use disorders identification test consumption (AUDIT C)
| Scoring system | ||||||
|---|---|---|---|---|---|---|
| Questions | 0 | 1 | 2 | 3 | 4 | Score |
| How often do you have a drink containing alcohol? | Never | Monthly or less | 2–4 times per month | 2–3 times per week | 4 or more times per week | |
| How many units of alcohol do you drink on a typical day when you are drinking? | 0–2 | 3–4 | 5–6 | 7–9 | 10 or more | |
| How often have you had 6 or more units if female, or 8 or more if male, on a single occasion in the last year? | Never | Less than monthly | Monthly | Weekly | Daily or almost daily | |
A total of 5 or more is a positive screen; 0–4 indicates low risk; 5–7 indicates increasing risk; 8–10 indicates higher risk; 11–12 indicates possible dependence. Based on: Public Health England, 2020b
A difficult aspect of offering lifestyle advice to people who have any of the aforementioned conditions is that they may feel otherwise well. This may not incentivise them to change any of their habits and, therefore, suggesting a reduction or change in diet and/or alcohol, as well as increasing exercise, can prove problematic. Health professionals have a duty of care not to alarm our patients but to educate them to make informed choices about their health. Certainly, enlightening them of the risk of NAFLD and how this can develop into NASH, fibrosis and cirrhosis can incentivise them to act. Practice nurses are best placed to undertake this role. However, each patient must be treated individually and encouraged to adopt lifestyles to suit them. For example, suggesting that they commence vigorous exercise would be unsuitable to those unused to exercise, but highlighting that gardening, housework, walking around shops, dancing or walking are also exercise, may be beneficial for some.
For those at risk of type 2 diabetes, referring them to the NHS diabetes prevention programme may be beneficial (NHS England, 2022). This is a 9-month, evidence-based lifestyle change programme. For people diagnosed with type 2 diabetes, keeping their blood glucose levels at optimal levels is key. For insulin resistance and type 2 diabetes, some limited evidence suggests reducing carbohydrate intake can be useful, as recent trials reveal that if people adhere to a ketogenic diet for up to 2 years this can reverse their metabolic syndrome, which in turn reduces their inflammatory markers (Ebbeling et al, 2022). Approximately 8% of trial participants had complete remission in their diabetes (O'Neill, 2020; Ebbeling et al, 2022). However, ketogenic diets tend to be high fat and moderate protein and it conflicts with NHS (2019) healthy eating advice, The Eatwell Guide.
One simple piece of health promotion advice that may be easily adhered to is to drink caffeinated coffee (see Treatment for more information), a minimum of four cups a day. Obviously, this would only be suggested if the person enjoyed coffee and not proffered to someone who was sensitive to caffeine (Mortimore, 2021), but evidence does suggest this might be of benefit.
CPD REFLECTIVE PRACTICE:
- How could you identify more cases of non-alcoholic fatty liver disease (NAFLD) in your practice?
- Think about a specific patient that may be at risk of NAFLD. What specific, tailored lifestyle advice could you give to them to reduce their risk?
- How will this article change your clinical practice?
KEY POINTS:
- Non-alcoholic fatty liver disease (NAFLD) is an umbrella term used to describe a build-up of fat in the liver, known as steatosis
- If left untreated, steatosis can develop into the more serious form of non-alcoholic steatohepatitis (NASH), where the liver becomes inflamed, and over time can further develop into fibrosis and cirrhosis
- Obesity is associated with the development of NAFLD
- Any patient who falls in the obese category and/or has type 2 diabetes or insulin resistance and/or is diagnosed with metabolic syndrome should be tested for NAFLD
- Health promotion in the form of lifestyle advice is the mainstay of treatment, with an emphasis on weight reduction and healthy diet
Conclusion
NAFLD is the over-arching term used to describe the development of steatosis in the liver which, if left untreated, can in some people develop into the more serious form of NASH – fibrosis and cirrhosis. Risk factors for developing NAFLD are metabolic syndrome, obesity, dyslipidaemia, insulin resistance or type 2 diabetes. With a huge increase in obesity and type 2 diabetes in the UK, there is reason to surmise there will be many people with undiagnosed NAFLD. Nurses are well placed to offer lifestyle advice to reduce the risk of developing NAFLD and NASH. It is important that their patients are forearmed with information to incentivise them to take action regarding diet, exercise, alcohol consumption and, if living with diabetes, ensuring good glycaemic control. Therefore, knowing about this condition and how it is now a global concern will aid practice nurses to offer all patients at risk lifestyle advice and encouragement.