1. Introduction

Thus, key issues in NAFLD patients are the differentiation of NASH from simple steatosis and identification of advanced hepatic fibrosis. Until now, liver biopsy has been the gold standard for identifying these 2 critical end points, but has well-known limitations, including invasiveness; rare but potentially life-threatening complications; poor acceptability; sampling variability; and cost. Furthermore, due to the epidemic proportion of individuals with NAFLD worldwide, liver biopsy evaluation is impractical, and noninvasive assessment for the diagnosis of NASH and fibrosis is needed. Although much of the work remains to be done in establishing cost-effective strategies for screening for NASH, advanced fibrosis, and cirrhosis, in this review, we summarize the current state of the noninvasive assessment of liver disease in NAFLD, and we provide an expert synthesis of how these noninvasive tools could be utilized in clinical practice. Finally, we also list the key areas of research priorities in this area to move forward clinical practice.

Fatty liver or non-alcoholic fatty liver disease (NAFLD, steatosis) is a disease in which there is an excessive accumulation of fats (mainly triglycerides) in the liver. Normally, there is a certain amount of fat in the liver, but under the influence of certain pathological factors, the balance between the synthesis and utilization of fats may be disturbed 1. The content of triglycerides in NAFLD can reach 40% of the mass of the liver (with a norm of about 5%). We studied NASH Clinical Research Network participants 21 years or older, not receiving pharmacologic therapy, from whom 2 or more liver biopsies and data on alcohol use within 2 years of the initial biopsy were available. Alcohol consumption was evaluated at study entry using the Alcohol Use Disorders Identification Test and Skinner Lifetime Drinking History questionnaires. At each follow-up visit participants were asked about alcohol use frequency, number of drinks on a typical day, and frequency of heavy drinking. The association between baseline drinking status and changes in fibrosis stage, NASH histology, and the NAFLD Activity Score and its individual components were evaluated by analysis of covariance. The association between change in drinking status and change in histology was evaluated using adjusted logistic regression. 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 unraveled, 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 summarizes 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.

SMF has a senior clinical research mandate from the Fund for Scientific Research (FWO) Flanders (1802154 N) and has acted as advisor and/or lecturer for Roche, Gilead, Abbvie, Bayer, BMS, MSD, Janssen, Actelion, Astellas, Genfit, Inventiva, Intercept, Genentech, Galmed, Promethera, Coherus, NGM Bio and Julius Clinical. GM served as Advisory Board member for Sanofi, Novartis, Astra-Zeneca, Intercept and Pfizer, and participated in clinical trials by Sanofi, Eli Lilly, Gilead, GENFIT and Intercept. AK has received project grants from Novartis and Intercept. MW has nothing to disclose in relation to this publication. RD has received project grants from Novartis and Intercept. JVL received research grants from Gilead Sciences and MSD, and speaker fees from Genfit, Gilead Sciences, MSD, Intercept Pharmaceuticals and Janssen, outside of this work. SZS has nothing to disclose in relation to this publication. KH has nothing to disclose in relation to this publication. LB serves as an Advisory Board member for Novo Nordisk. GF has nothing to disclose in relation to this publication. DD served as Advisory Board member and lecture for Novo Nordisk, Sanofi, BI, Astra-Zeneca, and participated in clinical trials by, Novo Nordisk, Eli Lilly, Sanofi and BI. EW has nothing to disclose in relation to this publication. MK has nothing to disclose in relation to this publication. JW has nothing to disclose in relation to this publication. GK has nothing to disclose in relation to this publication. SV has nothing to disclose in relation to this publication. MU has nothing to disclose in relation to this publication. JM has nothing to disclose in relation to this publication. CL has nothing to disclose in relation to this publication. Please refer to the accompanying ICMJE disclosure forms for further details.

Fatty liver disease or steatosis is the first stage of non-alcoholic fatty liver disease (NAFLD). As the disease progresses, it can progress to non-alcoholic steatohepatitis (NASH), in which inflammation is added to pre-existing steatosis.If the disease is left untreated, the patient may later develop fibrosis (replacement of liver connective tissue), which eventually develops into cirrhosis, and in rare cases, into hepatocellular carcinoma (liver cancer).Therefore, it is so important to see a doctor as early as possible so that the disease is diagnosed at the stage of steatosis, a condition that is reversible with comprehensive and timely treatment.

NAFLD is part of the metabolic syndrome characterized by diabetes, or pre-diabetes (insulin resistance), being overweight or obese, elevated blood lipids such as cholesterol and triglycerides, as well as high blood pressure. Not all patients have all the manifestations of the metabolic syndrome. Less is known about what causes NASH to develop. Researchers are focusing on several factors that may contribute to the development of NASH. These include:

• Oxidative stress (imbalance between pro-oxidant and anti-oxidant chemicals that lead to liver cell damage)

• Production and release of toxic inflammatory proteins (cytokines) by the patient’s own inflammatory cells, liver cells, or fat cells

• Liver cell necrosis or death, called apoptosis

• Adipose tissue (fat tissue) inflammation and infiltration by white blood cells

• Gut microbiota (intestinal bacteria) which may play a role in liver inflammation

NAFLD is a very common disorder affecting and may affect as many as one in three to one in five adults and around one in ten children in the United States. Obesity is thought to be the most common cause of fatty infiltration of the liver. Some experts estimate that about two thirds of obese adults and half of obese children may have fatty liver. About 2 to 5 percent of adult Americans and up to 20 percent of those who are obese may suffer from the more severe condition NASH. The number of children who have NASH is not known. The presence of type 2 diabetes and other conditions associated with insulin resistance, such as polycystic ovarian syndrome are know risk factors for the development of fatty liver and NASH. People with risk factors for fatty liver are often overweight or obese, and can have diabetes, or high levels of triglycerides/cholesterol in their blood. People with these risk factors should have their liver tests checked at least once per year. Those who are found to have elevated liver tests or possible fat in their liver on an abdominal ultrasound, or other imaging study, should be evaluated for possible fatty liver in addition to other causes of elevated liver tests. Once fat is identified in the liver, other causes of liver fat such as drinking too much alcohol, certain medications, and other liver diseases must be checked for before making a diagnosis of fatty liver. The next step is to determine whether the patient with fatty liver has only fat within their liver (also called steatosis), where scarring of the liver is rare or non-alcoholic steatohepatitis (NASH) with both fat and inflammation in the liver that over time can cause scarring in the liver. The most accurate way to figure this out is to perform a liver biopsy, a procedure where a small needle is inserted through the skin after numbing medicine is given to obtain a small piece of the liver for examination under a microscope. A pathologist then interprets the biopsy sample and determines whether NASH is present and, if so, whether any liver damage or scarring has taken place. There are a growing number of alternatives to liver biopsy that can also provide much of the same information without requiring needle insertion into the liver. These include measuring liver stiffness and fat content of the liver with elastography testing through the use of a specialized ultrasound (Fibroscan®) or MRI scan. Special blood tests or a combination of routine blood tests can also be used to evaluate for possible liver scarring in patients with NAFLD. Because none of these tests are perfect, patients with fatty liver are advised to discuss the risks and benefits of these tests with their doctor to decide which tests are best in their situation. In general, it is most beneficial to do a combination of tests to see if they all point to the same degree of fat in the liver and liver scarring. If the tests point to more significant scarring in the liver, your doctor may recommend a liver biopsy.

2. Treatment of NAFLD/NASH

In addition to good control of diabetes and high cholesterol/triglycerides when present, the most effective treatment for fatty liver, either NAFLD or NASH, involves changes in how you eat and live including weight loss, increasing your exercise, eating a balanced diet, and avoiding alcohol. Losing a small amount of body weight has been shown to improve liver biopsy results in those with NASH in addition to having a beneficial effect on blood sugars, blood pressure, and cholesterol levels. Various diets can lead to a reduction in liver fat, as long as there is a decrease in calories eaten in a day compared to a person’s daily required calories to maintain their current weight, with a goal of 500 fewer calories daily. Individuals should try to exercise 30 minutes or greater per day at least 5 times a week. However, both losing weight and maintaining weight loss can be difficult for many patients to achieve with lifestyle changes alone. In these instances, a doctor may prescribe a type of weight loss medication or may refer patients for a weight loss procedure or surgery. While there are currently no U.S. Food and Drug Administration (FDA) approved medications for treatment of NASH specifically, several are being studied and medicines to improve liver scarring in patients with NASH and fibrosis may soon be available to patients. In general, these experimental medications target different areas in the pathway of fat accumulation in the liver, associated inflammation, and scar tissue formation.