This patient guideline is intended for all patients at risk of or living with non-alcoholic fatty liver disease (NAFLD). NAFLD is the most frequent chronic liver disease worldwide and comes with a high disease burden. Yet, there is a lot of unawareness. Furthermore, many aspects of the disease are still to be unravelled, which has an important impact on the information that is given (or not) to patients. Its management requires a close interaction between patients and their many healthcare providers. It is important for patients to develop a full understanding of NAFLD in order to enable them to take an active role in their disease management. This guide summarises the current knowledge relevant to NAFLD and its management. It has been developed by patients, patient representatives, clinicians and scientists and is based on current scientific recommendations, intended to support patients in making informed decisions.

Abbreviations: ALD, alcohol-related or alcoholic liver disease; ASH, alcoholic steatohepatitis; BMI, body mass index; CAP, controlled attenuation parameter; CT, computed tomography; CVD, cardiovascular disease; EASD, European Association for the Study of Diabetes; EASL, European Association for the Study of the Liver; EASO, European Association for the Study of Obesity; FIB-4, fibrosis-4 index; FXR, farnesoid X receptor; GLP-1 RAs, glucagon-like receptor 1 agonists; GP, general practitioner; HCC, hepatocellular carcinoma; HDL, high-density lipoprotein; LDL, low-density lipoproteins; MRE, magnetic resonance elastography; MRI, magnetic resonance imaging; NAFL, non-alcoholic fatty liver; NAFLD, non-alcoholic fatty liver disease; NASH, non-alcoholic steatohepatitis; NASH CRN, NASH Clinical Research Network; NIT, non-invasive test; SMART, specific, measurable, achievable, relevant, timely; T1D, type 1 diabetes; T2D, type 2 diabetes

The purpose of this patient guideline

This guideline is intended for all patients at risk of or living with non-alcoholic fatty liver disease (NAFLD). NAFLD is a serious condition. It is important that you develop a full understanding of it. This has several advantages: first, it enables you to take an active role in your own healthcare. Second, you develop a better understanding of what the doctor is discussing with you. Third, you can monitor your condition and assess the success of various measures yourself. This guide will help you do that. It has been developed by patients, patient representatives, clinicians and scientists and is based on current scientific recommendations. It cannot and should not replace the individual consultation with your medical team but should support you in making informed decisions.

1. Introduction

a. What kind of organ is the liver? Where is it located? What is its function?

The liver is a large organ on the right-hand side of the body, located in the upper right quadrant of your abdomen. The normal weight of an adult liver is about 1,200–1,500 g. The liver is mostly covered and protected by the lower part of your ribcage (Fig. 1). About 20% of your blood volume per minute passes through the liver via the portal vein (75%) and hepatic artery (25%).

Fig. 1

The liver is a large organ on the right-hand side of the body, located primarily in the upper right quadrant of the abdomen.

The liver is mostly covered and protected by the lower part of your ribcage.

What does your liver do? The liver, as the chemical factory of your body, performs an extraordinarily complex set of functions to keep the body in a healthy condition. It receives blood from the gut via the portal vein, which carries most of the nutrients absorbed after a meal. Thus, the liver plays an important role as the first point where nutrients are filtered and further processed. For example, the liver has a key role in handling sugars, proteins and fats. After transformation, the liver releases the building blocks for energy and growth (i.e. substrates like sugar, fat and proteins) when required by organs. When you have just eaten and you have energy substrates that are not immediately needed as fuel, the liver will process these extra sources of energy. They can then be stored in the liver and elsewhere in your body, for example in the fat tissue, until your body needs them.

This also means that the liver plays an important role in the regulation of blood sugar (glucose) and lipid levels. Lipids refer to total and several subtypes of cholesterol, but also to triglycerides, which are another type of fat molecule that circulates in the blood. The term blood lipids also encompasses lipoproteins, which are larger composite structures of fat molecules and proteins.

The liver also produces many key proteins that your body needs to function normally like albumin, a protein that acts as a carrier for many molecules that need to be transported in the blood, and proteins needed for blood clotting. Your body continuously renews most of its structures, resulting in a lot of breakdown products. Along with the kidneys, the liver helps the body to get rid of these waste products.

Furthermore, the liver produces bile, a fluid that is stored in the gallbladder. During a meal, the gallbladder will contract, and this will cause the bile to drain into the gut (Fig. 1); there the bile salts will help to break down and absorb the fat molecules in your food. Part of the bile remains in the gut and is excreted in stool. This journey of the bile allows your body to get rid of several toxic substances (including alcohol) and excess cholesterol via the liver. Bile fluid contains the breakdown product of blood, bilirubin (which has a yellow colour), and also waste products from drug and alcohol metabolism. It is a way to get rid of too much cholesterol. Bile salts play a role in the metabolism of glucose and are therefore important for health. The liver also plays a role in the breakdown of many medications and other chemicals. Finally, the liver helps fight infections by filtering harmful organisms as they circulate in the blood, especially those entering the body via the gut.

The liver thus plays a central role in total body function. Consequently, its microscopic structure is complicated. Your liver carries out these important activities in silence: there are not many pain sensors in the liver and therefore liver diseases are often not painful, which can be a reason why a chronic liver disease remains undiagnosed for a long period of time. However, some livers can be more sensitive to pain, and some patients do experience a vague uncomfortable feeling or even pain from a chronic liver problem. This is due to the pressure on the capsule of the liver that has pain sensing nerves.

b. What is non-alcoholic fatty liver disease or NAFLD? What is the difference between NAFLD and non-alcoholic steatohepatitis (NASH)?

Steatosis means accumulation of fat in the cells. When this accumulation occurs in liver cells, it is called liver steatosis or fatty liver. There are different types of fat storage in cells. The type of storage that is relevant to NAFLD is fat (mainly triglycerides) that is stored in droplets. The size of these droplets can vary, but they are mostly large. Consequently, they fill up the whole inner part of the cell, pushing other parts of the cell to the cell border. This type of steatosis is called macrovesicular steatosis.¹

NAFLD is a fatty liver disease and the acronym stands for non-alcoholic fatty liver disease.¹ It is a condition in which too much fat is stored in the liver cells. As explained in Section 1.a, your liver is a key organ involved in energy regulation. What your liver is not supposed to do, however, is to store excess energy in the form of fat. The liver stores only a small amount of energy, namely some carbohydrate in the form of glycogen, but not fat. In some animals there is a small amount of fat in the liver in the fasting state, but that is not the case in humans.² Storing excess energy as fat is the role of your body’s fat tissue (adipose tissue).³ A healthy human liver hence contains few or no fat droplets. If there are fat droplets in more than 5% of the liver cells, this is considered as abnormal or pathological. In people with NAFLD, more than 5% of liver cells contain these fat droplets.

The accumulation of fat in the liver in the context of the disease called NAFLD is in most cases due to a combination of eating more calories than the body needs and leading a more sedentary (inactive) lifestyle. Therefore, it occurs most commonly, but not always, in association with being overweight/having obesity.^4,5 Another group of people at risk are people living with diabetes, more often type 2 diabetes (T2D), or earlier stages of altered glucose handling in the body.⁶ Abnormal levels of blood lipids or high blood pressure (arterial hypertension) are also associated with an increased risk of having NAFLD.⁷ Abnormal levels of blood lipids can mean too many triglycerides. It can also mean unhealthy levels of cholesterol. Cholesterol is not transported as such in the blood, but is carried around in lipoproteins, those composite structures of lipid and proteins that were previously mentioned. Several types of lipoproteins circulate in the blood and they all have their specific function. The most prominent ones for the transport of cholesterol are high-density lipoproteins (HDL) and low-density lipoproteins (LDL). Your body needs both, in the right concentration, and also in the right balance. Lower HDL concentrations and/or higher LDL concentrations are harmful, in particular for your blood vessels.

All these conditions are called metabolic factors and a combination of them is referred to as the metabolic syndrome. Several definitions of the metabolic syndrome have been developed over time and are summarised in Table 1.[8], [9], [10], [11] The metabolic syndrome is associated with an increased risk of developing numerous other health problems and diseases.

Table 1

Definitions and criteria of the metabolic syndrome.CriteriaWHO (1999)⁸NCEP (2001)⁹IDF (2005)¹⁰Joint societies (2009)¹¹Required for diagnosisImpaired glucose tolerance or diabetes and/or insulin resistanceNoneCentral obesity as defined belowNoneNumber of featuresTwo other factors≥3 of the below≥2 of the below≥3 of the belowCentral obesityWaist–hip ratio of >0.9 in men, >0.85 in women or BMI ≥30 kg/m²Waist circumference ≥102 cm in men, ≥88 cm in womenWaist circumference ≥94 cm European men; ≥90 cm South Asian or Chinese men; ≥80 cm womenWaist circumference – population-specific definitionsTriglycerides≥150 mg/dl (1.7 mmol/L)≥150 mg/dl (1.7 mmol/L)≥150 mg/dl (1.7 mmol/L) or treatment for high triglycerides≥150 mg/dl (1.7 mmol/L) or treatment for high triglyceridesHDL-cholesterol<40 mg/dl (1 mmol/L) in men, <50 mg/dl (1.3 mmol/L) in women<40 mg/dl (1 mmol/L) in men, <50 mg/dl (1.3 mmol/L) in women<40 mg/dl (1 mmol/L) in men, <50 mg/dl (1.3 mmol/L) in women<40 mg/dl (1 mmol/L) in men, <50 mg/dl (1.3 mmol/L) in womenHypertension≥140/90 mmHg≥135/85 mmHg or treated hypertension≥135/85 mmHg or treated hypertension≥135/85 mmHg or treated hypertensionGlucosen.a.110 mg/dl (6.1 mmol/L)≥100 mg/dl (5.6 mmol/L) or diagnosed with type 2 diabetes mellitus≥100 mg/dl (5.6 mmol/L), or drug treatment for diabetesMicroalbuminuriaAlbumin–creatinine ratio >30 mg/g; albumin excretion rate >20 μg/minn.a.n.a.n.a.

IDF, International Diabetes Federation; n.a., not applicable; NCEP, National Cholesterol Education Program; WHO, World Health Organization; BMI, body mass index; HDL, high-density lipoprotein.

It is important to highlight that steatosis is not always a result of metabolic factors. It can also be caused by alcohol.¹² Furthermore, it can be caused by some drugs such as methotrexate (a drug used to treat rheumatoid arthritis). Steatosis can also be seen in some other liver diseases, such as Wilson’s disease (a very rare disease in which the body stores excess copper) and some variants of hepatitis C (a chronic inflammation of the liver caused by the hepatitis C virus).^13,14

The term non-alcoholic fatty liver disease was coined in 1980, but observations of people with too much fat in their liver cells and no other cause of steatosis (e.g. alcohol consumption) were already being made in the 19th century.¹⁵ At the time, doctors did not understand the metabolic causes of the steatosis, so they named the disease according to what it was not. As alcohol was by far the most common and best-known cause of steatosis at the time, this disease was called non-alcoholic. In contrast to most diseases for which the name refers to the cause, this disease was hence named to indicate what it was not. Therefore, the name of this disease is not without problems (see Section 1d) and is under discussion.^16,17

In many cases, the extra fat in the liver cells does not seem to be harmful or affect how well the liver works. This is called simple or isolated fatty liver, or non-alcoholic fatty liver (NAFL, without the “D” for disease). When the liver cells containing the fat droplets become inflamed and damaged, it is called steatohepatitis, so non-alcoholic steatohepatitis or NASH (Fig. 2).^13,14 The term hepatitis refers to inflammation of the liver, whatever the cause. As outlined later, NASH is the subtype of NAFLD that carries more long-term risks (Section 2).

Fig. 2

The different subtypes of NAFLD and their relationships with the severe consequences of the disease.

NAFLD is the overarching term. If there is mainly only steatosis, we call it simple steatosis or isolated steatosis (NAFL). If there is also liver cell damage and inflammation, we call it steatohepatitis (NASH). The separation is not static, so you can have NAFL and evolve to NASH, and also the other way around. The active disease can evolve to more severe liver injury and ultimately cirrhosis. Cirrhosis means advanced scarring of the liver, but even in these conditions, the liver can continue to function (compensated cirrhosis). Some people with cirrhosis will, however, evolve to poor liver function, which is called decompensated cirrhosis. NAFLD is also associated with the risk of developing liver cancer (HCC). As you can see from the figure, cirrhosis and decompensated cirrhosis mostly occur in association with NASH, whereas patients with NAFL have a lower (but not zero) risk. For HCC, the risk is the highest if you have cirrhosis, but there is still a risk in patients without cirrhosis and even without NASH. The magnitude of the boxes does not give any indication of the magnitude of the risk (please refer to the text for risk estimates). HCC, hepatocellular carcinoma; NAFL, non-alcoholic fatty liver; NAFLD, non-alcoholic fatty liver disease; NASH, non-alcoholic steatohepatitis.

When your liver is damaged, it tries to repair itself by creating new, healthy tissue. If the damaging process continues, the liver’s ability to create enough healthy tissue and clean-up the damage may be exhausted. As a consequence, scar tissue will develop and can accumulate. This scarring is called fibrosis. Some (but not all) patients with NASH will develop fibrosis over time called progressive fibrosis. Both the amount of scar tissue and the distribution pattern (exactly where in the liver the fibrosis is located at the microscopic level) are important.^1,18 Together, the amount and pattern indicate how severe the damage is. This is most commonly expressed by a scale of five stages (from 0 to 4), based on what is seen on a liver biopsy (see Section 5.c). This scale was developed by the NASH Clinical Research Network (NASH CRN) in the United States and was later incorporated into the Steatosis-Activity-Fibrosis (SAF) system.[18], [19], [20] As both the amount and the distribution pattern of the scar tissue determine the stages, this is not a linear scale: stage 2 does not mean that there is twice as much scar tissue as in stage 1. Stage 4 is called cirrhosis. Cirrhosis means that your liver tissue is becoming very scarred, with a surface that is no longer flat but instead bumpy and “nodular”. Although some scarring can still be reversible at this stage, the changes become more and more irreversible. The liver can sometimes function quite normally even with stage 4 fibrosis/cirrhosis. This is called compensated cirrhosis. Once the liver is not able to function properly, or other liver-related problems arise (e.g. liquid accumulation in the abdomen (ascites), yellowing of the skin and whites of eyes (jaundice)), it is called decompensated cirrhosis (Fig. 2).²¹

It should be noted that sometimes the liver does not function properly even when there is no cirrhosis, and any type of reduced liver function can have a major impact on your health and wellbeing. If the disease gets worse or better, you can change from one stage to another.²² Frequently used terms are also significant fibrosis, which means a fibrosis stage of at least 2 on a liver biopsy, and advanced fibrosis, which means a fibrosis stage of at least 3.^1,18,19 Besides the most widely used staging based on the scale from 0 to 4 (referred to as F0 to F4), other classification systems with other scales exist, which can lead to confusion. If you have a diagnosis of fibrosis with a given “F” stage, your doctor should explain exactly what this means for you.

The terminology might appear confusing because of the different abbreviations used. To summarise, NAFLD is the overarching term, incorporating both NAFL and NASH, with a risk of increasing fibrosis and ultimately cirrhosis (Box 1). You can have NAFL at one time, then develop NASH but later go back to NAFL, depending on how the disease evolves and how well the risk factors are managed. Thus, NAFLD is dynamic and its activity (i.e.the extent of damage to liver cells and inflammation) can fluctuate over time (Fig. 2).²²

Box 1

The terminology of non-alcoholic fatty liver disease.

c. What is the cause of NAFLD/NASH? How do you get it?

As mentioned earlier (Section 1.b), NAFLD can have many causes, so before a diagnosis can be made, other causes of steatosis should be evaluated. The most frequent of these alternative causes is related to the consumption of alcohol (the terms ALD, for alcohol-related liver disease, and ASH, alcoholic steatohepatitis, are used). NAFLD, by definition, is NOT linked to alcohol excess. This implies that you should not be diagnosed with NAFLD if you drink more than the upper limits that have been set or have had a history of past excess alcohol intake. The drinking limits are most often defined by a weekly consumption of less than 14 units for women and 21 for men (1 unit equals 8 g of alcohol, the meaning of alcohol expressed in units is explained in Box 2). These limits correspond to the amount of alcohol that is known to cause steatosis by itself.²³ You should also not binge drink (binge drinking is defined as ≥4 drinks/day for women and ≥5 drinks/day for men).²³ These limits do not mean that alcohol consumption below these limits is harmless. It is indeed highly questionable whether alcohol consumption at any level can be considered safe. It just means that a consumption of alcohol below these limits is probably not causing steatosis. It might, however, still carry a risk for other health problems, in particular cancer.^12,24

Box 2

Alcohol consumption.

While both NAFLD and ALD cause inflammation, fibrosis, and cirrhosis, they are different diseases with different causes and different treatment options.^12,13 It is important to note that you can have both at the same time.

Indeed, although other diseases that can cause fatty liver need to be ruled out when diagnosing NAFLD, you should be mindful that it is possible to live with more than one factor causing the liver damage. Examples of these other conditions that induce fatty liver are drug-associated steatohepatitis (DASH), chemotherapy-associated steatohepatitis (CASH) and toxicity-associated steatohepatitis (TASH or toxicant-associated steatohepatitis).

Over time, the medical community’s understanding of NAFLD has gradually increased. Nowadays, it is well known that metabolic factors play the most prominent role in explaining why many people develop fatty livers. There is a strong link between NAFLD and obesity.^4,5 There is also a strong link with the way the body responds to insulin (T2D and pre-diabetes).³ Unhealthy levels of blood lipids and high blood pressure (hypertension) are also risk factors. As mentioned, all these elements are components of the metabolic syndrome (Box 3 & Table 1).¹¹ These are general observations that do not always explain the full picture in a given individual. It is not always clear why fat builds up in the liver in some people. Genetic background may play a part, making some people more likely to be affected by NAFLD than others.^5,[25], [26], [27]

Box 3

The metabolic syndrome.

One of the key mechanisms has to do with the fact that humans evolved over millions of years to live in conditions where there was a lack of food. That is why we are so fond of sugar, and why we have fat tissue to store extra calories. But in our modern society, food is generally available. We also need less of it because we are less physically active than our ancestors. This combination causes the quantity of our fat tissue to increase. However, there is a limit to the amount of fat that our fat tissue can store. If our food intake exceeds the storing capacity of fat tissue, the fat will build up elsewhere, including in the liver. NAFLD is hence strongly linked with unhealthy lifestyles, mainly from consuming excess calories, having an unhealthy diet and from a lack of physical activity (Fig. 3). Genetic and other factors will also determine how much fat an individual can store.²⁸ These factors also have an influence on how vulnerable our liver is when it must deal with excess fat and its consequences.

Fig. 3

The body harbours different types of fat or adipose tissue.

(A) The fat that is inside the abdominal cavity and in close contact with both the gut and the liver is called intra-abdominal or visceral fat. The fat just beneath the skin is called subcutaneous fat. Intra-abdominal fat is more active, in terms of metabolic processes that are going on inside the cells. The intra-abdominal fat tissue is also active in the production of signals that help the body regulate its energy metabolism. It is thus not just a storage space, but also an active regulator of your body’s energy handling. (B) When this fat tissue is overwhelmed and the fat cells become very swollen, the fat tissue will become inflamed because there is not enough blood supply to and hence not enough oxygen in these too swollen fat cells. This leads to damage and dysfunction of this fat tissue. This inflamed fat tissue will release harmful substances into the blood that can then damage the liver. Subcutaneous fat is less reactive. It stores your energy reserves, which is important to protect us from the destructive consequences of calorie excess. However, there is a limit to that storage capacity too. When your excess calories exceed this storage capacity, the fat will need to go somewhere else.

There are different types of fat tissue (Fig. 3). The fat that is inside the abdominal cavity and in close contact with both the gut and the liver is called intra-abdominal fat or visceral fat. The fat just beneath the skin is called subcutaneous fat. Intra-abdominal fat is more active, in terms of metabolic processes that are going on inside the cells. The intra-abdominal fat tissue is also active in the production of signals that help the body regulate its energy metabolism.³ It is thus not just a storage organ, but also an active regulator of your body’s energy handling. This type of fat is, however, also more prone to being overwhelmed. When this happens and the fat cells become very swollen, the fat tissue will become inflamed because of insufficient blood and hence oxygen supply. This leads to damage and dysfunction of this fat tissue. As a consequence, this inflamed fat tissue will release harmful substances into the blood that can then damage the liver.^3,29Subcutaneous fat is less reactive. It stores your energy reserves, which is important to protect us from the destructive consequences of calorie excess. However, there is a limit to that storage capacity. This limit in storage capacity differs from one individual to another.

Although we now better understand the metabolic drivers of the disease, many issues remain. For the same lifestyle habits and risk factors, some people develop NAFLD, NASH and ultimately cirrhosis, while others do not.⁵Additionally, some people have no or only very mild risk factors, but nevertheless develop advanced disease. The reasons behind these differences are currently poorly understood. Genetic factors only explain a fraction of the variation between individuals and much more research is needed to understand these individual differences.^5,30,31

d. Why are we still calling it NAFLD/NASH? Are there alternative names?

As the understanding about NAFLD has grown, some experts argue that NAFLD/NASH are no longer appropriate names. Metabolic-associated fatty liver disease (MAFLD) has been suggested by some experts as an alternative name, to reflect the fact that a metabolic disorder is the key factor in the development of the disease.¹⁶ However, there is not yet universal support for this proposal.¹⁷One of the reasons is that the disease also occurs and progresses in some people who do not have metabolic disorders.³²

One of the problems with the term NAFLD, as explained in Section 1.b, is that the name tells you what it is not, instead of telling you what it is. Furthermore, strictly speaking, the diagnosis of NAFLD requires the other well-known causes of steatosis to be excluded.¹³But metabolic risk factors for NAFLD can be present together with harmful alcohol consumption (or another well-established cause of steatosis). In this case, the fatty liver has two causes at the same time. It has also been demonstrated that both these causes together can intensify disease progression to more severe liver disease and liver cancer.[33], [34], [35], [36] In such mixed cases, it can be difficult to identify the leading cause, and it seems fair to indicate both NAFLD and ALD. This helps avoid focusing on and treating only one of the causes. It also avoids stigmatising diagnoses that are incorrect or that only tell part of the story, which would also create the risk of an incomplete and ineffective treatment plan.

For these reasons, there is support for changing the name in order to have a name that tells you what the disease stands for. MAFLD is the leading alternative, with a consensus process ongoing.

e. What is the difference between NASH and ASH?

NASH is, by definition, NOT linked to alcohol excess, whereas ASH is linked to a current and/or past history of excess alcohol consumption (see Section 1.c).¹³

Significant alcohol consumption can lead to steatosis, steatohepatitis, and fibrosis.¹²Under the microscope, this looks very much the same as what is seen in NAFLD. As outlined in Section b, c, NAFLD has been described as the presence of steatosis and steatohepatitis, much like ALD, but occurring in people who do not drink excess alcohol.¹³ In most of these patients, NAFLD is related to the presence of metabolic risk factors. Those who have metabolic risk factors and drink alcohol can have both NAFLD and ALD.³⁶Using a terminology like MAFLD would solve the problem of “non-alcoholic” and the exclusionary nature of the definition, but the concept remains the same: both diseases can co-exist and lead to a fatty liver disease of mixed origin. Which of the factors is the major cause, is not always clear. Someone with metabolic risk factors and moderate alcohol consumption should not be labelled with ALD. Instead, they should be described as having potentially mixed cause fatty liver disease – with one or other being the main driver of damage.

2. Why is NAFLD/NASH important?

a. What is the impact in terms of liver disease? What will happen to me?

If NAFLD is detected and managed early enough, it is possible to reduce the amount of fat in your liver, which may slow down or even stop the damage, and eventually allow your liver to fully recover.

NAFLD with only fat accumulation in the liver cells and no or only minimal signs of liver cell damage or inflammation, called simple or isolated fatty liver or NAFL (Fig. 2) (you will also encounter the term ‘early NAFLD’), does not usually cause any harm, but if it is not managed, can progress to NASH, which is a more serious condition.³⁷ Most people with NAFLD have isolated fatty liver.³⁸

NASH is more serious than isolated fatty liver because there is inflammation in the liver, and it starts to become damaged (Fig. 3). This is sometimes referred to as early NASH. This inflammation can lead to fibrosis, which means scar tissue is forming inside the liver. This is often referred to as fibrotic NASH.

Fibrosis can lead to cirrhosis, which means that large strands of scar tissue alter the liver structure, with regenerating liver tissue in between. This is called NASH-cirrhosis. Because of these strands of fibrosis and zones of liver cell regeneration, the liver becomes very scarred and the surface becomes irregular and bumpy or “nodular” (See Section 1.b). This irregular and bumpy appearance of the liver is a hallmark of cirrhosis. In cirrhosis, the main functions of the liver can initially be preserved (compensated cirrhosis, Fig. 2). The liver will, however, struggle more and more to function properly as the disease progresses. Eventually, liver function can be so poor that problems occur (decompensated cirrhosis) to the point where liver function becomes insufficient to support life (liver failure) (Fig. 2, Fig. 3).

Liver cancer (hepatocellular carcinoma, HCC) is another potential consequence of NAFLD. This risk of developing HCC is well known in patients with cirrhosis from other causes and is now also well documented in NASH-cirrhosis.^39,40 Importantly, HCC has also been reported in patients with NASH who do not have cirrhosis, and even in patients with NAFL.^41,42 It is not clear how big this risk is exactly, but in general, the more severe the disease is, the higher the risk is. The highest risk is when you have cirrhosis. The presence of comorbidities like obesity, or the presence of other liver-damaging factors like alcohol, also contribute to the risk of developing HCC.^39,43

b. How quickly does NAFLD progress?

The damage caused by NAFLD can take many years to progress and is most frequently described in five stages depending on the amount and distribution pattern of fibrosis found (Section b, 5):

In general, NAFLD fibrosis gets worse by one stage every 14 years.⁴⁴ NASH fibrosis gets worse by one stage every seven years. These are only average figures. Progression is not linear and can be different according to the stage.²² A recent analysis of patients in clinical trials showed that 20% of patients with F3 progressed to cirrhosis in two years, while 20% of patients with cirrhosis, but with good liver function and without complications of liver disease, developed more severe cirrhosis-related liver problems (decompensated liver cirrhosis) in two years (Fig. 2).⁴⁵ These figures are called the 20% ‘rule’.⁴⁶ In some cases, the liver can be damaged much faster than these average figures, and up to 1-in-5 patients with fibrosis progression are rapid progressors (Fig. 5).^44,47

Fig. 5

The current understanding of NAFLD is that most patients only have fatty liver, without liver cell damage and inflammation (NAFL).

Some patients will evolve to NASH, wherein steatosis is accompanied by liver cell damage and inflammation. This can go along with the accumulation of scar tissue or fibrosis. In a subset of patients with NASH, more and more scar tissue will accumulate and ultimately result in cirrhosis. Patients with cirrhosis but with good liver function can evolve to a cirrhosis-related more severe liver problem (decompensated cirrhosis). A liver cancer (HCC) can develop at any stage, but the risk of HCC is higher when the NAFLD is more severe. Usually, the evolution of the disease is slow, but some patients can be rapid progressors. NAFLD increases the risk of developing diabetes. NAFLD also increases the risk of diseases of the heart and blood vessels (CVD). NAFLD may also increase the risk of several types of cancer (including bowel cancer) and the development of kidney problems. CVD, cardiovascular disease; HCC, hepatocellular carcinoma; NAFL, non-alcoholic fatty liver; NAFLD, non-alcoholic fatty liver disease; NASH, non-alcoholic steatohepatitis.

There are major differences in the way the disease develops and progresses between individuals.⁵ This could be due to fluctuations in the severity of the metabolic risk factors as well as the impact of diverse (unhealthy) lifestyles, in addition to genetic factors.^22,48This is something we currently do not fully understand.

c. How does NAFLD affect general health?

Your liver is a large organ, able to carry out a complex set of functions (see Section 1.a). Large blood vessels connect your liver with the rest of the body. When your liver is not working properly, the metabolism works only to a limited extent, toxic substances may remain in the body and other damaging substances may even be produced. It is understandable that NAFLD not only damages the liver, but other organs too.

Research shows that NAFLD increases the risk of developing T2D, and if you already have T2D, it makes controlling your T2D more difficult.⁴⁹ NAFLD also increases the risk of cardiovascular (heart) disease by damaging the walls of blood vessels.⁵⁰ NAFLD influences the build-up of mineral deposits or calcifications on the vessel walls, which is called atherosclerosis. It also causes damage to the heart, mainly the heart muscle and the system that regulates heart rhythm. NAFLD may also increase the risk of several types of cancer (including bowel cancer)⁵¹ and the development of kidney problems (Fig. 5).^52,53

d. In which stage of NAFLD do problems occur?

It is still unclear whether all patients with NAFLD are at risk for all these serious problems, or if these complications are mainly restricted to patients with NASH (Box 4). Studies have shown that the severity of liver fibrosis is the most important predictor of what will happen to someone with NAFLD.⁵⁴People with NAFLD who have more severe fibrosis were shown to have a higher chance of developing serious health problems or dying. These serious health issues obviously arise from liver disease, but also, and even more frequently, from non-liver-related diseases. Diseases of the heart and blood vessels (cardiovascular disease, CVD) are the most frequent problems encountered. Factors other than fibrosis (observed at the time of diagnosis) appear to be less predictive of health events later in life.⁵⁵ Liver fibrosis does not directly cause your heart to stop working. Having liver fibrosis is, however, a sign that your liver is not able to function in a highly effective way. This leads to long-term problems for the liver and/or other organs.

Box 4

Consequences of NAFLD.

NAFLD, non-alcoholic fatty liver disease; NASH, non-alcoholic steatohepatitis.

Based on other scientific data, it is likely that the process of liver damage and inflammation (NASH) is the true driving force behind subsequent health problems.^56,57 This seems to be true for the formation of fibrosis and the progression towards cirrhosis, as well as for the consequences outside of the liver.⁴⁴

Because of these considerations, clinical trials to test possible treatments, especially drugs, currently focus on patients with NASH and fibrosis, and not on less severe stages of the disease.[58], [59], [60]

e. Impact of the NAFLD/NASH on health-related quality of life

The impact of NAFLD is not limited to physical issues, but also affects health-related quality of life (Box 5). The concept of health-related quality of life has been defined by the Center for Disease Control (CDC) as “an individual’s or a group’s perceived physical and mental health over time”.⁶¹ Specific questionnaires have been developed to get further insight into the health-related quality of life of patients with NAFLD/NASH.^62,63

Box 5

Health-related quality of life.

NAFLD can clearly have an impact on one’s quality of life.^64,65 The associated conditions of T2D, obesity, unhealthy blood lipid levels (dyslipidaemia) and CVD also negatively impact health-related quality of life.

People with NAFLD in the early stages of disease generally have no symptoms and their quality of life is not impaired. The burden of NAFLD on health-related quality of life becomes progressively more important with advancing disease, when fatigue and impaired physical conditions related to NASH (see Section a, b, 11) accumulate and have a significant impact on daily life.^66,67 In the more severe stages of the disease, the physical and psychological consequences of liver disease add to those of the metabolic comorbidities (as mentioned: obesity, T2D, dyslipidaemia, CVD). So clearly, health-related quality of life deteriorates as NAFL progresses to early NASH, NASH-cirrhosis and liver failure, or liver cancer (regardless of how severe the underlying NAFLD is).

The impact of NAFLD may be made even worse by the stigma associated with obesity⁶⁸and/or T2D, problems of shame/guilt linked to presumed alcoholism, and difficulties accepting the diagnosis.

Although your day-to-day activities may not be affected for a long time, the costs of NAFLD increase linearly as fibrosis and liver damage progress.^69,70 This is driven by hospital admissions, the costs of treating co-existing conditions, and personal costs (e.g.loss of employment).

3. Basic data on epidemiology and natural history

a. Who gets NAFLD/NASH?

It is estimated that between 17–46% of European adults have NAFLD (on average, around 25%). It affects people of all ages, including children.⁶ This condition is directly linked to chronic excess calorie consumption, lack of physical activity/exercise and being overweight/having obesity (Fig. 3).¹³

Thus, you are more likely to have NAFLD if you have obesity and T2D, with NAFLD occurring in nearly 9 out of 10 (90%) people living with obesity (depending on the severity of the excess body weight) and in 5–7 out of 10 (50–70%) people living with T2D (in relation to being overweight and having poor metabolic control,³⁸ or if you have high lipid or LDL cholesterol levels in the blood) (Fig. 6).^4,71 The number of people with NAFLD increases progressively with age. Genes and ethnic origin are also important, with more people of Asian and Spanish origin being affected than people of African origin.^40,72

Fig. 6

It is estimated that 25% of European adults have NAFLD.

You are, however, more likely to have NAFLD if you have obesity and T2D, with NAFLD occurring in nearly 8 to 9 out of 10 (80 to 90%) people living with obesity and in 5-7 out of 10 (50-70%) people living with type 2 diabetes. The number of people with NAFLD increases progressively with age. NAFLD, non-alcoholic fatty liver disease; T2D, type 2 diabetes.

Some people with NAFLD have a normal body weight (up to 20% of NAFLD patients, which is then called lean NAFLD) or are overweight but do not have obesity (20%).^32,73 These numbers vary across the world, being as low as 25% in South-East Asian countries, and up to 50% elsewhere,⁷⁴ depending on how obesity is defined in each country.⁷⁵ The concept of lean NAFLD is, however, somewhat misleading and simplistic. The definition of lean is based on body mass index (BMI – your weight divided by your height squared) but does not take into account how the weight is distributed in the body (fat vs. muscle, intra-abdominal fat vs. subcutaneous fat) (Box 6). It also simply draws a line at 25 kg/m² (or 23 kg/m² for Asian people): if you are just below that line, you are lean; if you are just above, you are overweight. In reality, BMI is a continuum. Lean people with NAFLD often have some abdominal fat accumulation or other subtle metabolic abnormalities.⁷⁵ Lean NAFLD hence refers to the presence of NAFLD in people that have few obvious metabolic risk factors. They might have some excess body fat but still be lean according to the BMI criteria. We do not know why such individuals develop NAFLD. Anyhow, if the medical community can find a positive definition of the disease based on which metabolic abnormalities you must have, this oversimplified concept of lean NAFLD will disappear. For the time being, it is better to talk about NAFLD in lean people, instead of lean NAFLD.

Box 6

Body mass index.

BMI, body mass index.

b. How frequent are the complications?

Based on current scientific knowledge, it is known that in most patients with simple or isolated fatty liver, the liver remains stable over time (see also 2.a). In contrast, if you have NASH, you are at a relatively high risk of worsening liver injury.⁴⁴ NASH occurs in 1 in 4-5 patients with NAFLD, i.e. between 1.5% and 6.5% of the general population, but this figure is much higher (in some studies over 60%) in patients with T2D.⁷¹ Severe fibrosis is estimated to occur in around 1.5% of the general adult population⁷⁶ and in up to 10% of adults with T2D. Severe fibrosis means at least F3 on a liver biopsy, often referred to as “advanced fibrosis”. Half of these patients will ultimately develop cirrhosis.^71,77

There is some understanding of how NAFLD progresses, thanks to research studies using liver biopsies. Studies using two biopsies at different time points indicate that the liver damage – in terms of fibrosis – gets worse over time if you have more active steatohepatitis, so more aggressive liver damage and inflammation.⁵⁷ As mentioned in Section 2.a, on average NAFLD fibrosis worsens by one stage every 14 years and NASH fibrosis gets worse by one stage every seven years.⁴⁴ The data on the progression of the disease are summarised in Fig. 7.

Fig. 7

How does NAFLD evolve over time?

Not everybody with NAFLD will develop cirrhosis. The estimated percentages of patients who will evolve stepwise to a more severe disease stage are depicted here. F1-2-3, stage of fibrosis 1-2-3; HCC, hepatocellular carcinoma; NAFLD, non-alcoholic fatty liver disease; NASH, non-alcoholic steatohepatitis.

These figures should be treated with some caution because they are based on studies that looked at the biopsies of patients and not everyone needs to have a liver biopsy. It is possible that the individuals who had liver biopsies may have already had more advanced NAFLD and so the aforementioned figures may overestimate the number of people who progress to advanced fibrosis and cirrhosis.