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Department of Gastroenterology and Hepatology, Antwerp University Hospital, Antwerp, BelgiumLaboratory of Experimental Medicine and Paediatrics (LEMP), Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, BelgiumInflaMed Centre of Excellence, University of Antwerp, Antwerp, BelgiumTranslational Sciences in Inflammation and Immunology, University of Antwerp, Antwerp, Belgium
School of Public Health, Faculty of Social Welfare and Health Sciences, University of Haifa, Haifa, IsraelDepartment of Gastroenterology and Hepatology, The Tel-Aviv Medical Center, Tel-Aviv, Israel
Newcastle NIHR Biomedical Research Centre, Newcastle Upon Tyne Hospitals NHS Foundation Trust, Newcastle Upon Tyne, UKTranslational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
Department of Internal Medicine, Division of Gastroenterology and Hepatology, Maastricht University Medical Centre, Maastricht, the NetherlandsSchool of Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht University, Maastricht, the Netherlands
Department of Family Medicine, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, IsraelWorld Organization of Family Doctors (WONCA)European General Practice Research Network (EGPRN)Israel Association of Family Physicians, IsraelLeumit Health Services, Tel Aviv, Israel
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.
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. 1The liver is a large organ on the right-hand side of the body, located primarily in the upper right quadrant of the abdomen.
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.
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.
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.
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.
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.
World Health Organization Definition, diagnosis and classification of diabetes mellitus and its complications: report of a WHO consultation. Part 1: diagnosis and classification of diabetes mellitus.
Expert Panel on Detection, Evaluation and T of HBC in A Executive summary of the third report of the national cholesterol education program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (adult treatment panel III).
Harmonizing the metabolic syndrome: a joint interim statement of the international diabetes federation task force on epidemiology and prevention; national heart, lung, and blood Institute; American heart association; world heart federation; international.
World Health Organization Definition, diagnosis and classification of diabetes mellitus and its complications: report of a WHO consultation. Part 1: diagnosis and classification of diabetes mellitus.
Expert Panel on Detection, Evaluation and T of HBC in A Executive summary of the third report of the national cholesterol education program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (adult treatment panel III).
Harmonizing the metabolic syndrome: a joint interim statement of the international diabetes federation task force on epidemiology and prevention; national heart, lung, and blood Institute; American heart association; world heart federation; international.
≥150 mg/dl (1.7 mmol/L) or treatment for high triglycerides
≥150 mg/dl (1.7 mmol/L) or treatment for high triglycerides
HDL-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 women
Hypertension
≥140/90 mmHg
≥135/85 mmHg or treated hypertension
≥135/85 mmHg or treated hypertension
≥135/85 mmHg or treated hypertension
Glucose
n.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 diabetes
Microalbuminuria
Albumin–creatinine ratio >30 mg/g; albumin excretion rate >20 μg/min
n.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.
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).
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.
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.
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).
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. 2The 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.
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.
Utility and appropriateness of the fatty liver inhibition of progression (FLIP) algorithm and steatosis, activity, and fibrosis (SAF) score in the evaluation of biopsies of nonalcoholic fatty liver disease.
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).
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.
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.
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).
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.
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.
While both NAFLD and ALD cause inflammation, fibrosis, and cirrhosis, they are different diseases with different causes and different treatment options.
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.
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).
Harmonizing the metabolic syndrome: a joint interim statement of the international diabetes federation task force on epidemiology and prevention; national heart, lung, and blood Institute; American heart association; world heart federation; international.
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.
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.
(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.
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.
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. 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.
Additionally, 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.
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.
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.
But 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.
Moderate alcohol consumption is associated with advanced fibrosis in non-alcoholic fatty liver disease and shows a synergistic effect with type 2 diabetes mellitus.
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).
Under 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.
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.
Using 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.
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.
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.
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):
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.
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).
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).
Many factors determine if you will develop more severe liver disease and how quick the evolution is. Luckily, many patients will not evolve to severe liver disease and many steps in the evolution are reversible with adequate management. NAFL, non-alcoholic fatty liver; NASH, non-alcoholic steatohepatitis.
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.
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.
This 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.
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)
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.
People 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.
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.
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.
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.
U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) Noncirrhotic nonalcoholic steatohepatitis with liver fibrosis: developing drugs for treatment. Guidance for industry.
European Medicines Agency Committee for Medicinal Products for Human Use Reflection paper on regulatory requirements for development of medicinal products for chronic non infectious liver diseases.
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”.
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.
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 obesity
This condition is directly linked to chronic excess calorie consumption, lack of physical activity/exercise and being overweight/having obesity (Fig. 3).
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,
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.
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%).
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.
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.
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.
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.
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.
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.
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.
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.
Studies also demonstrate that, besides patients whose disease progresses, there are also patients who improve and others who simply remain stable.
Disease progression is hence difficult to predict in an individual case.
4. Who should be tested for NASH and how? How should tests results be interpreted?
a Who should be screened?
The question of whether people can and should be actively screened for NAFLD is an important one. From a scientific point of view, there are several requirements that need to be fulfilled before screening can be recommended. These include the availability of cost-effective and safe screening methods, and that something can be offered to you (such as a treatment) if you screen positive for a certain condition.
Not all these conditions are met in the field of NAFLD, which explains why there is no universal screening guideline and no universal screening algorithm everybody agrees upon.
Nevertheless, although there is no global consensus, there is a growing understanding that physicians should at least consider screening patients who are at risk of having NAFLD.
This is probably particularly true for patients at risk of developing NASH and/or fibrosis. These risk categories also include people with chronically elevated liver blood tests.
‘Chronically’ usually means for more than six months, so at least two blood samples six months apart are needed. It may include people living with T2D or being overweight/having obesity, people with metabolic syndrome (see Table 1 for definition and criteria of this entity), and people with CVD.
Some of these risk categories include large groups of people. It is sometimes difficult to pinpoint who is affected: should, for example, all patients living with T2D be screened? In what frequency? Or what exactly is CVD? So, this needs fine-tuning in the future.
but it is probably too early to formulate a clear recommendation (Box 7). Patients with T1D who are overweight/have obesity and have other features of metabolic syndrome may also be at risk and would potentially benefit from screening.
As mentioned, there is no universal consensus on whether you need to screen, and if so, how. There are many unanswered questions to date, reflected by variations in screening policy and methodology.
As this is a slowly evolving disease, focus should probably lie on picking up the people that are most at risk of developing NAFLD-related problems in the near future. Therefore, most of the screening efforts should focus on NASH and at least F2 fibrosis, or on fibrosis alone (F2 or more, or F3 or more).
Most screening strategies rely on a blood test score, a liver ultrasound or a liver stiffness assessment, or a combination of these.
The combination strategy can be deployed in one instance. It is also possible to perform tests sequentially. This means that the second test is only performed if the first one is positive or gives a result in the grey zone (Fig. 8), which signifies an unclear result. As mentioned, there is no universal strategy. Any strategy should consider available resources and how healthcare is organised in a local setting. The UK National Institute for Health and Care Excellence guideline
There is no international consensus on the optimal screening strategy. Tests can be combined at one instance. Another possibility is to use several different tests sequentially: the second test is only performed if the first one is positive or gives an unclear result. NAFLD, non-alcoholic fatty liver disease.
If you are screened according to a particular algorithm, there should be a management and follow-up plan ready to accompany the result. All patients need a plan. The intensity of the management and further work-up (which could include a liver biopsy in selected cases) can differ according to the screening results (see Section 8). The exact meaning of the results should be clearly explained to you in order to avoid misinterpretation. This is extremely important to avoid giving you unjustified reassurance or the opposite, to saddle you with unnecessary stress and fear.
d Should tests be repeated over time?
There is no international scientific consensus on how exactly patients at risk of or with NAFLD should be monitored over time (see also Section 8).
The more the screening test result indicates a higher likelihood of liver damage, the more intensive the follow-up should probably be. For example, you are overweight, and you are screened: the test result tells you that you have a very low likelihood of having NASH with at least F2 fibrosis. This is reassuring, but you should still be supported to lose weight. This is because, even though your screening result is negative this time, significant liver disease might develop later. If you remain overweight, it seems appropriate to repeat the screening at a later time. Currently, there is no precise recommendation that is universally applicable on this issue. It is, however, obvious that even if initial screening is negative, a repeat assessment at a later date is appropriate if the risk factors remain. The precise timing and modality of the repeat screening will depend on the result of the previous assessment and on local practices.
5. How can the disease and its severity be diagnosed?
a What are the symptoms?
Most adults do not notice any symptoms in the early stages of NAFLD and find out they have it when they are being tested for something else, such as an annual check-up or during tests for other conditions such as T2D or gallstones. The liver blood tests are usually abnormal, but not always.
Diagnostic accuracy and prognostic significance of blood fibrosis tests and liver stiffness measurement by FibroScan in non-alcoholic fatty liver disease.
If abnormal, they are usually only slightly elevated, which should not be considered as a sign of mild disease. Surprisingly, the degree of abnormality of the blood tests does not reliably predict the severity of liver injury. This means that liver tests may be normal or show only minor elevations and you still can have advanced disease.
You can experience fatigue or tiredness, general lethargy, and right-sided abdominal discomfort or an ache on the right side of your tummy just under the ribs. These symptoms are sometimes reported and might get worse over time as NAFLD progresses. However, other causes of these symptoms need to be ruled out. Nevertheless, evidence is accumulating that NAFLD independently contributes to fatigue and reduced physical capacity, which can be explained by the crucial role of the liver in energy metabolism.
You can experience more severe symptoms when your liver becomes more severely scarred (i.e. if you have cirrhosis), such as unexplained weight loss, yellowing of the skin and the whites of the eyes (jaundice), itchy skin, and swelling in the legs or tummy.
Because NAFLD starts off without noticeable symptoms, your doctor may perform tests if you have risk factors associated with getting NAFLD (like T2D or metabolic syndrome) to see if you have it.
b Who should diagnose NAFLD/NASH?
The diagnosis of NAFLD/NASH can be performed either by your general practitioner (GP), your doctor for internal medicine or diabetes, or your liver specialist (“hepatologist”). The GP or your doctor for internal medicine will take your medical history and can order blood tests and an ultrasound scan. These evaluations and knowledge about other conditions you may have can give a first indication of whether or not you may have NAFLD or NASH. Either your GP or doctor for internal medicine can decide if you should have an appointment with a liver specialist. A liver specialist should confirm the diagnosis, especially for those with advanced stage disease.
c Liver biopsy as the gold standard
A liver biopsy is an invasive procedure that takes very small samples of liver tissue for investigation (about 1/50,000th of your liver). It allows the doctors to assess different areas within the liver and can provide information about the number of liver cells containing fat droplets (steatosis), the degree of liver cell damage and inflammation (the “activity” of the disease) and the degree of liver fibrosis (the “stage” of the disease).
The presence of steatosis is the first criterion to define fatty liver disease. The human liver can contain a few fat droplets, but they are rare. The degree of liver steatosis on the biopsy is expressed as the number of liver cells (“hepatocytes”) that contain those droplets. A few hepatocytes (up to 5%) containing fat droplets is not considered abnormal or pathological. If more than 5% of the hepatocytes contain fat droplets, then this is no longer considered normal, such that this defines what is a fatty liver (see Section 1.b).
The amount of liver fat is then further graded as 1 (up to 1/3 of the cells laden with fat droplets, mild steatosis), 2 (between 1/3 and 2/3, moderate steatosis) and 3 (>2/3 of the cells laden with fat droplets, severe steatosis).
Utility and appropriateness of the fatty liver inhibition of progression (FLIP) algorithm and steatosis, activity, and fibrosis (SAF) score in the evaluation of biopsies of nonalcoholic fatty liver disease.
Whether the amount of fat in the liver (i.e. the grade of steatosis) is important in terms of liver damage and long-term prognosis, is not completely clear. If steatosis is the only abnormality, without signs of liver damage, it is called simple or isolated steatosis. Although some worsening of the disease in terms of development of scar tissue has been described, the risk of this is much lower than in people who have liver cell damage and inflammation on top of the steatosis (Fig. 2).
Liver cell damage and inflammation constitute what is called the “activity” of the disease. This is the active process that drives the development of scar tissue and the worsening of the disease towards cirrhosis and liver failure (end-stage liver disease). The latter may become an indication for liver transplantation (See Section 2.a).
With a liver biopsy, a typical swelling of the liver cells (what is called ballooning of the liver cells) and the presence of inflammatory cells are the two most important hallmarks of liver cell damage in the context of fatty liver.
Many other features and details can also be assessed by pathologists (these are the specialist doctors that examine tissues under the microscope) and can help to grade the severity of the underlying damaging process. Several scoring systems have been developed over time to indicate the level of disease activity.
The third cardinal feature and piece of information provided by the biopsy is the presence of scar tissue. Scar tissue formation is in fact a normal wound healing process. If the damage is, however, continuously present and if there is an imbalance between damage and repair, progressively more and more scar tissue will accumulate.
This affects normal liver function, e.g. the exchange between the blood and the liver cells. It will also disturb, in the advanced stage, the normal microscopic architecture of the different liver cell types and blood vessels. This leads to cirrhosis. As for steatosis and activity, scoring systems have been developed over time to express the severity of the fibrosis as a figure on a scale (See Section b, a) (Box 8).
Utility and appropriateness of the fatty liver inhibition of progression (FLIP) algorithm and steatosis, activity, and fibrosis (SAF) score in the evaluation of biopsies of nonalcoholic fatty liver disease.
This severity is not only a matter of the amount of scar tissue but also the pattern of fibrosis, i.e. how the scar tissue is located in between the different cell types and structures of the liver. The most widely used scale goes from 0 to 4, 0 meaning there is no fibrosis, whereas 4 equals cirrhosis. The scale is not linear, because both amount and pattern determine the exact stage. So, stage 2 does not mean that you have twice as much scar tissue as in stage 1: there is more scar tissue, but also the distribution pattern is different. This scale is specific for NAFLD. In other liver diseases, fibrosis can be distributed in a different pattern. Biopsy-based stage 2 in NAFLD is hence not the same as stage 2 in viral hepatitis.
Utility and appropriateness of the fatty liver inhibition of progression (FLIP) algorithm and steatosis, activity, and fibrosis (SAF) score in the evaluation of biopsies of nonalcoholic fatty liver disease.
Cirrhosis refers to a situation where, at the microscopic level, fibrous strands breach the normal structure and create fibrous bridges (see also Section b, a). There are also changes in the blood vessels and nodules of newly formed cells emerge to replace what has been lost. All this leads to nodular reorganisation of the liver, i.e. cirrhosis. Cirrhosis is hence a structural alteration of the liver, and not per se a functional one. Liver function, at least gross liver function, can be preserved in early cirrhosis. Of course, when it becomes more severe, cirrhosis will ultimately lead to defective liver function.
Besides giving information on all these different aspects of the disease, a liver biopsy can also be very useful to exclude other liver diseases. If you have risk factors for NAFLD and you have elevated liver blood tests, you could still have another type of liver disease. A liver biopsy can be helpful to diagnose these other liver diseases as well as NAFLD.
As with every investigation in medicine, liver biopsy is not perfect. As mentioned, a classical biopsy represents only about 1/50,000th of the total amount of liver tissue. And although the liver in NAFLD is more or less diffusely damaged, there can be some differences in severity between different areas in the liver. This means that if you take a liver biopsy of two different liver regions, some differences may be observed between the two pieces under the microscope.
This potential difference between two different areas of the liver is called sampling variability. In NAFLD, these differences are overall rather minor. For fibrosis, it is known that a difference of one stage between two biopsies is not uncommon, but a difference of two stages is rare.
Also, the experience of the pathologist who examines the biopsy is of importance. These limitations (and all techniques in medicine come with some limitations) must be acknowledged. Furthermore, a liver biopsy is an invasive procedure and comes with some risks.
Guidelines on the use of liver biopsy in clinical practice from the British Society of Gastroenterology, the Royal College of Radiologists and the Royal College of Pathology.
When performed by experienced doctors, the likelihood of a good quality biopsy is high and the risks are low, but never zero.
d Can the biopsy be replaced by something else? What about other less invasive liver tests?
It is currently not possible to obtain all the information that a liver biopsy provides (degree of steatosis, activity and fibrosis, other markers of disease severity and diagnosis of other liver diseases) with a single alternative.
It is, however, to some extent possible to get an idea of some aspects of the disease using one or more non-invasive techniques (Box 9). It is important to note that liver biopsies have been used as the reference method in the development of almost all of these techniques As the liver biopsy is in itself not perfect, this approach might over- or underestimate the accuracy of a non-invasive technique. It is nevertheless currently the best way to get as close as possible to an accurate assessment of the liver abnormality that is being studied.
The development of non-invasive biomarkers (non-invasive tests, NITs) in NAFLD is most advanced for the assessment of the presence and severity of steatosis and for the assessment of the severity of the fibrosis.
The field is not as advanced for the non-invasive assessment of disease activity, i.e. whether there is steatohepatitis and how severe or active the NASH is.
Steatosis
The presence of steatosis can be assessed with imaging techniques. An ultrasound of your abdomen, comparing the brightness of your liver to the grey scale of your right kidney, is accurate in identifying the presence of steatosis if steatosis affects more than 30% of the liver cells.
Minor degrees of steatosis can be missed on ultrasound, but moderate and severe steatosis can be diagnosed with more than 90% accuracy. The brightness of your liver can also be scored on ultrasound. This scoring correlates to some extent with the severity of steatosis on liver biopsy, although this is not very accurate.
Ultrasound can diagnose steatosis, but not steatohepatitis and not the stage of fibrosis, and can diagnose cirrhosis if your liver looks nodular.
The Fibroscan® device (see also the next section on fibrosis) can also assess the amount of liver fat, via the determination of the controlled attenuation parameter or CAPTM.
Screening diabetic patients for non-alcoholic fatty liver disease with controlled attenuation parameter and liver stiffness measurements: a prospective cohort study.
A computed tomography scan can also be used to diagnose steatosis, comparing your liver with your spleen. As with ultrasound, it cannot diagnose the presence of liver damage and inflammation, nor fibrosis.
Magnetic resonance imaging (MRI) is the most accurate technique to diagnose the presence of liver fat, and it can be used to quantify the levels of liver fat.
Liver fat on MRI is also expressed as a percentage, but not the percentage of liver cells laden with fat droplets, rather the percentage of total liver weight that is composed of fat. Up to 5% is also considered normal. A percentage of 30% corresponds to very severe steatosis, as it is a percentage of total weight; as such, this percentage cannot be directly compared to observations made on a liver biopsy. MRI is so accurate in assessing the presence of liver fat and in quantifying it,
Agreement between magnetic resonance imaging proton density fat fraction measurements and pathologist-assigned steatosis grades of liver biopsies from adults with nonalcoholic steatohepatitis.
that it is considered the reference method (gold standard) for this particular feature, but it is still mainly used for research purposes.
Besides imaging, there are scores based on a combination of tests, mainly blood tests that have been shown to have some value in diagnosing the presence of liver fat and its severity. Examples are the Fatty Liver Index, the SteatoTestTM or the Liver Fat Score.
Imaging is currently not able to accurately visualise scar tissue or fibrosis. Technical evolution might, however, make this possible in the future. Imaging can be used to assess liver stiffness, which is a physical characteristic of your liver. Liver stiffness is the opposite of liver elasticity, so liver stiffness measurement is called elastometry or elastography. The latter means a mapping of liver elasticity. A healthy liver is smooth in texture (elastic), but when diseased, it can become stiffer. This stiffness can be influenced by the presence of fibrosis, but also by inflammation and swelling. Also, the blood flowing through the liver must be taken into account. After a meal, when more blood goes to the gut and the liver, the liver is a little stiffer than in fasting conditions.
All these factors can affect the stiffness of your liver. This means that liver stiffness does not simply equal fibrosis. Nevertheless, it has been shown that liver stiffness and the stage of fibrosis do correlate.
Diagnostic accuracy and prognostic significance of blood fibrosis tests and liver stiffness measurement by FibroScan in non-alcoholic fatty liver disease.
Liver stiffness values have been assessed using fibrosis stage on liver biopsy as the reference method or gold standard. Scoring systems for fibrosis on liver biopsy are not the same for every liver disease. Therefore, values of liver stiffness corresponding to fibrosis stages can be different from one liver disease to another. For a given stage of fibrosis, the corresponding range of liver stiffness measurements is also broad. This means that there is a lot of overlap in liver stiffness values between two consecutive stages of fibrosis diagnosed on liver biopsy. This implies that a liver stiffness measurement cannot be interpreted as a precise measurement of the fibrosis stage on the liver biopsy.
Because of that, your liver stiffness value is compared to threshold values or cut-offs. These cut-offs are levels that indicate a high or low risk of a given level of fibrosis severity. The interpretation depends on the values that are used as cut-offs: with a low cut-off, you can be quite sure that if you are below that value, there really is no significant fibrosis; inversely, with a high cut-off, your likelihood of having more severe fibrosis or even cirrhosis is high, but never 100%.
The cut-offs are different whether you want to rule-in or rule-out a condition, so if you want to be sure that it is or that it is not present. The cut-offs are also different if you are looking for significant fibrosis, advanced fibrosis or cirrhosis. This is all quite complicated, and your doctor should tell you exactly what your liver stiffness value means. As explained, your liver stiffness does not tell you exactly which fibrosis stage you are in. It only tells you how likely you are to be “at least in a given stage of fibrosis”, or how certain you can be that your fibrosis is not so severe. Thus, the interpretation is quite complex and depends on multiple factors.
Several techniques to measure liver stiffness have been developed over time.
Most of them are based on ultrasound. A series of pulses are applied to the liver. Based on the return of the pulses these instruments can measure the stiffness of the liver. The most widely used is vibration-controlled transient elastography, which is the technique in the Fibroscan® device.
The liver stiffness scores are not comparable between these techniques. Hence, each technique has its own reference values and cut-offs. When mentioning a liver stiffness value, you need to know which technique has been used to understand the meaning of the result.
Comparison of laboratory tests, ultrasound, or magnetic resonance elastography to detect fibrosis in patients with nonalcoholic fatty liver disease: a meta-analysis.
Liver stiffness can also be measured by MRI, which is called magnetic resonance elastography (MRE). MRE maps the whole liver. MRE is considered the most accurate technique for liver stiffness measurement.
Magnetic resonance vs transient elastography analysis of patients with nonalcoholic fatty liver disease: a systematic review and pooled analysis of individual participants.
However, MRE is not widely available and is more costly and time consuming than ultrasound techniques.
Besides imaging, several individual blood parameters are available for basically the same purpose. There are several scores based on a combination of blood parameters to assess fibrosis (Box 10).
Diagnostic accuracy and prognostic significance of blood fibrosis tests and liver stiffness measurement by FibroScan in non-alcoholic fatty liver disease.
Some of these scores are based on routine blood tests and can easily be calculated by the lab or using online calculators that can be found on the internet.
Some blood tests and scores are offered commercially and come with an additional cost. Many of them are also still experimental but the interpretation of their results is comparable to liver stiffness measurements. Examples of tests and scores that are based on routine blood tests include the fibrosis-4 index (FIB-4)
A blood-based biomarker panel (NIS4) for non-invasive diagnosis of non-alcoholic steatohepatitis and liver fibrosis: a prospective derivation and global validation study.
ALT, alanine aminotransferase; AST, aspartate aminotransferase; BMI, body mass index; F0-1-2-3, stage of fibrosis 0-1-2-3; FIB-4, fibrosis-4 index; IFG, impaired fasting glycemia; IU, international units.
All these individual tests have their accuracy, depending on what you want to know. Combining test modalities clearly makes the overall result more accurate.
Without a biopsy, it is difficult to tell the difference between a simple or isolated fatty liver (steatosis) and a fatty liver with liver cell damage and inflammation (steatohepatitis). The assessment of this difference has been the most challenging part of developing non-invasive markers for NAFLD. This is also true for determining the severity of the steatohepatitis, what is called the activity of the NASH. One of the reasons is that the activity of the disease is closely linked to the degree of fibrosis. Changes in activity over time are linked with changes in fibrosis stage over time.
Therefore, if you analyse a marker for its relationship with fibrosis, this relationship will also be influenced by the presence at the same moment of inflammation and cell damage. This holds true for liver stiffness measurements as well as for blood-based markers and scores.
MRI-based techniques, such as multiparametric MRI, are most promising in this regard.
A blood-based biomarker panel (NIS4) for non-invasive diagnosis of non-alcoholic steatohepatitis and liver fibrosis: a prospective derivation and global validation study.
The FAST score, an approach combining liver stiffness measurement by Fibroscan®, steatosis assessment by CAPTM (on the same Fibroscan® device) and the liver blood test aspartate aminotransferase (AST), also seems to hold promise.
FibroScan-AST (FAST) score for the non-invasive identification of patients with non-alcoholic steatohepatitis with significant activity and fibrosis: a prospective derivation and global validation study.
However, further studies are required to determine the accuracy of these approaches.
Baseline assessment vs. follow-up
The techniques that have been discussed try to non-invasively assess the degree of steatosis, the stage of fibrosis or the activity of the steatohepatitis. Studies have compared these techniques with biopsies at one point in time. This type of comparison is called a cross-sectional analysis. How these tests evolve over time has not been well validated. It is also not known what a change in such a parameter over time really means. For example, if your liver stiffness goes down over time: what does that tell you about the lesions on your liver biopsy? Although it makes sense to think that the improvement in liver stiffness should correspond to a reduction in the amount of fibrosis, there is still very little scientific proof for that. This has to do with the fact that steatosis, steatohepatitis, and fibrosis are closely linked. As mentioned before, liver stiffness correlates with fibrosis, but is not determined by fibrosis alone. Liver stiffness can also be influenced by the presence of steatohepatitis.
But the fibrosis stage can still be the same. In summary, much more research is needed to know exactly what it means if non-invasive markers change over time.
Despite these limitations and knowledge gaps, these NITs are already frequently used. More studies are urgently needed to increase our understanding of how to work with these tools in the future. For the time being, changes over time should be interpreted cautiously.
One should also not forget the potential variability of tests. Before drawing any conclusion from an increase or a decrease of a given test over time, a repeated measurement is advisable to be sure that there is a consistent decrease or increase. And at best, any change over time can currently only be considered as a potential indicator, but by no means a proof, for a positive or negative evolution over time.
e Algorithms
The previous sections described the different techniques that can be used to diagnose NAFLD and its severity. Many patients are at risk of NAFLD, but only a small percentage of those with NAFLD will develop more severe disease.
It is therefore important to make an accurate diagnosis, or at least as accurate as possible. The biopsy provides the clearest overall picture, but as explained, the biopsy has its limitations. Some aspects of the disease can be diagnosed with alternative techniques. This makes it possible to have sufficiently accurate information without the need for a biopsy in many (but not all) cases.
There is no unique, globally applicable scheme or algorithm to make an accurate diagnosis, but generally the following principle applies: When you are suspected of having NAFLD on the basis of clinical history, examination and blood tests, the next step is an ultrasound scan (Fig. 8).
A fatty liver usually looks brighter-than-normal on the scan. Unfortunately, neither the blood tests nor routine scans can reliably distinguish between isolated or simple fatty liver and more severe disease with inflammation or scarring/cirrhosis.
The NITs that we discussed in the previous sections are relatively new ways of ruling out advanced liver disease.
This means that they are relatively accurate at telling you that you do not have the more severe forms of the disease. In this way, the tests may enable most people to avoid a liver biopsy. Validated scores like the FIB-4 or NAFLD fibrosis score can be used to calculate the risk of having severe disease and a liver stiffness assessment can also be performed – this also helps to predict whether a person has simple or isolated fatty liver disease or might have more advanced disease. Scores and liver stiffness measurements are often combined, or one is used as a confirmation of the other (sequential use).
If these tests are negative, they can quite accurately tell you that you have little chance of having more severe disease. So, in that case, they can reassure you. The opposite, namely a positive test telling you with certainty that you have a more severe form of NAFLD, is more difficult.
If these tests do not give a reliable answer, a liver biopsy may be needed. A liver biopsy may also be necessary if a high suspicion of advanced and/or active disease needs to be confirmed, or if other liver diseases need to be excluded.
6. If a diagnosis of NAFLD is established, what is the treatment?
If you are diagnosed with NAFLD, your doctor will talk to you about making healthy diet and lifestyle choices. This is the cornerstone of NAFLD treatment and should always be the first treatment option. There are currently no medicines to specifically treat NAFLD, although research is underway to develop them. Without specific drugs for treatment, weight loss is key, and this can be achieved through a combination of dietary changes and increasing physical activity/exercise levels. These changes can help to:
•
Reduce the amount of fat and inflammation in your liver. Even if your liver is scarred, there can be some improvement if you make and sustain lifestyle changes, given that the liver has the ability to regenerate.
•
Improve your metabolic profile and thereby lower your risk of CVD, T2D and liver cancer.
a Other liver diseases that can exist in conjunction with NAFLD should be looked for
As part of the diagnostic work-up, other causes of liver disease should be looked for and treated if they are present. If you have NAFLD you can also have another liver disease at the same time. Alcohol is discussed in Section 6.e. If multiple liver problems exist together, they often reinforce each other, and the disease may progress more rapidly. Therefore, it is important to identify other potential diseases, which can often be done with additional blood tests (see also Fig. 9) but may require a liver biopsy.
Fig. 9This flowchart represents a proposal of how to approach the challenge of diagnosing NAFLD if you have one or more risk factors for NAFLD.
b All cardiometabolic risk factors should be checked and treated according to their proper guidelines
As mentioned, there is a strong association between the metabolic syndrome, T2D, CVD and NAFLD (see Section b, c and Table 1). Therefore, it is important to check your weight, blood glucose, blood pressure and blood lipids (cholesterol, triglycerides) on a regular basis and manage these appropriately (there are separate guidelines for this
) to reduce your risk of CVD and T2D. If necessary, your doctor may prescribe specific medications, such as those to treat high blood pressure or elevated cholesterol.
c All other chronic diseases should be checked/excluded, including psychological diseases
NAFLD, but also the components of metabolic syndrome, are chronic diseases. They sometimes cause other chronic diseases or co-exist with other diseases. All these diseases are frequently treated by several different (specialised) physicians and other healthcare providers. Nevertheless, they are not strictly separated but frequently interact. This close entanglement of all these diseases, including psychological and psychiatric conditions, should not be minimised. Ideally, everything should be treated as part of the global management of your health (see also Section 6.g). Your family doctor and other first-line healthcare providers may help you with this and play an important role in keeping an overall view of all your health problems. If one of your health problems and diseases is not taken care of it could have a negative impact on the treatment of NAFLD or your other conditions.
d Maximum effort should be made to improve the factors that drive the disease: this is what is meant by lifestyle modification
Weight reduction, whichever way it is achieved, leads to improvements in your liver blood tests (liver enzymes), the amount of liver fat and liver inflammation, as well as the amount of scar tissue or fibrosis.
The impact of weight loss on liver improvement depends on the degree of weight reduction. A weight reduction of >5% is usually necessary to reduce liver fat, 7–10% to improve liver inflammation and >10% to improve fibrosis/scarring, although even lower reductions can be helpful.
Therefore, the guideline, jointly written by three scientific societies (the European Association for the Study of the Liver (EASL), the European Association for the Study of Diabetes (EASD), the European Association for the Study of Obesity (EASO))recommends a weight loss target of 7–10% if you are overweight or have obesity with NAFLD.
The favourable effects of moderate weight loss also extend to lean patients who do not have obesity-associated NAFLD. In this case, a 3% weight loss is likely to drive NAFLD remission.
Lifestyle changes that produce even modest results, such as a sustained weight loss of 5%, can induce clinically meaningful reductions in triglycerides and blood glucose. These reductions are important to prevent heart disease and T2D, respectively.
Weight loss can be achieved by any dietary method that reduces calorie intake. Many different types of diet have been shown to be effective for inducing weight loss, though there is no “magic” diet. You can choose a diet with health benefits that you feel able to follow in the long-term, guided by your doctor and/or dietician/nutritionist. For example, a low-carbohydrate diet appears to be similarly effective as a low-fat diet in reducing liver fat and the liver enzyme alanine aminotransferase longer term, as long as a 7% weight loss is achieved.
Impact of current treatments on liver disease, glucose metabolism and cardiovascular risk in non-alcoholic fatty liver disease (NAFLD): a systematic review and meta-analysis of randomised trials.
Saturated fat has been shown in several studies to have a reinforcing effect on liver fat accumulation. For example, in a study comparing the addition of muffins high in saturated fat vs. muffins high in unsaturated fat to the habitual diet there was a similar increase in body weight across both groups. Only the muffins with the high saturated fat, however, markedly increased liver fat, liver blood tests (liver enzymes) and serum lipids.
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