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The Importance of Noninvasive Screening in Non-Alcoholic Fatty Liver Disease

  • Authors: Rohit Loomba, MD, MHSc
  • CME / ABIM MOC Released: 12/1/2022
  • Valid for credit through: 12/1/2023
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Target Audience and Goal Statement

This activity is intended for diabetologists, endocrinologists, and gastroenterologists.

The goal of this activity is for learners to be better able to use available noninvasive tests for liver fibrosis in clinical practice.

Upon completion of this activity, participants will:

  • Have increased knowledge regarding the
    • Importance of risk assessment for liver fibrosis
    • Serum biomarkers used in noninvasive screening
  • Demonstrate greater confidence in their ability to
    • Use risk stratification scores for liver fibrosis


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  • Rohit Loomba, MD, MHSc

    Professor of Medicine
    University of California at San Diego
    Director of Hepatology
    Director, NAFLD Research Center
    San Diego, California, United States


    Rohit Loomba, MD, MHSc, has the following relevant financial relationships:
    Consultant or advisor for: Aardvark Therapeutics; Altimmune; Anylam/Regeneron; Amgen; Arrowhead Pharmaceuticals; AstraZeneca; Bristol Myers Squibb; CohBar; Eli Lilly; Galmed Pharmaceuticals; Gilead Sciences; Glympse Bio; HighTide; Inipharma; Intercept Pharmaceuticals; Inventiva; Ionis Pharmaceuticals; Janssen Inc.; Madrigal Pharmaceuticals; Merck; Metacrine, Inc.; NGM Biopharmaceuticals; Novartis; Novo Nordisk; Pfizer; Sagimet Biosciences; Terns Pharmaceuticals; Theratechnologies; Viking Therapeutics; 89bio
    Research funding from: Arrowhead Pharmaceuticals; AstraZeneca; Boehringer Ingelheim; Bristol Myers Squibb; Eli Lilly; Galectin Therapeutics; Galmed Pharmaceuticals; Gilead Sciences; Hanmi Pharmaceutical; Intercept Pharmaceuticals; Inventiva; Ionis Pharmaceuticals; Janssen Inc.; Madrigal Pharmaceuticals; Merck; NGM Biopharmaceuticals; Novo Nordisk; Pfizer; Sonic Incytes; Terns Pharmaceuticals
    Other: Co-founder of LipoNexus Inc.


  • Anne G. Le, PharmD

    Senior Medical Education Director, Medscape, LLC


    Anne G. Le, PharmD, has no relevant financial relationships.

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  • Susan L. Smith, MN, PhD

    Associate Director, Accreditation and Compliance, Medscape, LLC


    Susan L. Smith, MN, PhD, has no relevant financial relationships.

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The Importance of Noninvasive Screening in Non-Alcoholic Fatty Liver Disease

Authors: Rohit Loomba, MD, MHScFaculty and Disclosures

CME / ABIM MOC Released: 12/1/2022

Valid for credit through: 12/1/2023


Activity Transcript

Rohit Loomba, MD, MHSc: Hello, I'm Rohit Loomba, director of hepatology and director of the NAFLD Research Center and professor of medicine at the University of California at San Diego in San Diego, California. Welcome to this program entitled "The Importance of Noninvasive Screening in Non-Alcoholic Fatty Liver Disease," or NAFLD. Over the next 30 minutes or so I will review the importance of risk assessment for liver fibrosis in patients with NAFLD and discuss recent advances in the noninvasive diagnosis and risk stratification of NAFLD.

Why are we talking about NAFLD today? Because worldwide, NAFLD is rapidly becoming the most common cause of chronic liver disease. If you look at the epidemiology of non-alcoholic fatty liver disease, we think approximately 1 in 4 adults have non-alcoholic fatty liver disease worldwide. One billion people overall in the world may have non-alcoholic fatty liver disease. Did you know that there is a clear ethnic predisposition for NAFLD? NAFLD is much more common in Asian Indians and Hispanics than Caucasians. And African American are protected. What about who are the individuals who are at increased risk for developing non-alcoholic fatty liver disease? The most important risk factor is metabolic syndrome and components of metabolic syndrome including obesity, hypertension, hypertriglyceridemia, insulin resistance, and diabetes, especially type 2 diabetes and other features of metabolic syndrome. We have also discovered that there are certain genotypes that are associated with increased risk for developing non-alcoholic fatty liver disease, and these include PNPLA3, TM6SF2, and MBOAT7. We've also found out over the last few years that there are certain genotypes that might be protective, and these include HSD17B13.

How do we define non-alcoholic fatty liver disease? It's defined on either a liver biopsy or imaging evidence of hepatic steatosis where at least 5% of hepatocytes are infiltrated with hepatic fat in individuals who consume little or no alcohol without any other cause for liver disease or hepatic steatosis. Now, understanding natural history of non-alcoholic fatty liver disease is really important. We think about 80 million Americans may have non-alcoholic fatty liver disease and within those, the progressive form of NAFLD called non-alcoholic steatohepatitis occurs in about 15 to 20 million of those. The number 1 risk factor for mortality among patients with NAFLD is cardiovascular disease, number 2 is cancer, and liver disease jumps to the third leading cause of mortality. The majority of our patients with NASH will develop progressive liver disease over years, and we think the rate of fibrosis progression in patients with NASH is approximately 1 stage per 7 years. So, you can imagine it'll take somebody who doesn't have fibrosis today but has features of NASH on histology probably 3 to 4 decades to develop cirrhosis. Once you develop bridging fibrosis, which is stage 3 fibrosis, 20% of these patients may progress to cirrhosis over the next 2 to 3 years. Once you develop cirrhosis, the risk of developing hepatocellular carcinoma in patients with NAFLD exponentially increases. We think this risk is about 1.5% to 2% per year among those who have cirrhosis due to NAFLD. Now, some patients with NAFLD could develop hepatocellular carcinoma without going through cirrhosis. The risk of developing that is low, but we are trying to identify who are these patients who might develop hepatocellular carcinoma without growing through cirrhosis. Once patients have developed cirrhosis, the risk of liver-related mortality and morbidity exponentially increases, and these are the individuals who might need liver transplantation.

What do we know about the prevalence of advanced fibrosis among patients who have first-degree relatives who have advanced fibrosis due to NAFLD. And why are we bringing this topic up? Well, clinicians have thought that if somebody had family history of a particular disease, is there a higher risk of that disease in the offspring or first-degree relatives? Same thing was true, anecdotally noted in liver disease and NAFLD cirrhosis. So, we conducted a prospective study and looked at patients with cirrhosis and their first-degree relatives and found that the risk of advanced fibrosis was approximately 15%. And these data were then validated in an independent validation cohort from Finland. Using this totality of data, the new NAFLD practice guidance that was just recently discussed at the AASLD 2022 liver meetings, this has been added to a recommendation in the guidance statement, where if you have a first-degree relative with advanced fibrosis or cirrhosis, you should be screened for advanced fibrosis cirrhosis.

Why is liver fibrosis important in the setting of fatty liver disease? There's a clear link between disease activity, which is referred to as injury to the hepatocytes, and in the case of NAFLD, is related to fat deposition, insulin resistance and lipotoxicity, leading to ballooning degeneration and inflammation. This progressive injury, over time, could lead to activation of stellate cells, leading to fibrogenesis and progression of fibrosis. And some of these patients may go on to develop cirrhosis and then may develop complications due to cirrhosis.

This is a pooled meta-analysis that we did a few years ago that shows that the risk of liver-related mortality is linked to fibrosis stage. Others have confirmed these data, and this is now well validated and well accepted in the field that as stage of fibrosis increases in non-alcoholic fatty liver disease, the risk of liver-related mortality increases. The tipping point or the inflection point is considered to be stage 2 fibrosis or higher, and that we also refer to as sometime as significant fibrosis. Because of that, the new therapies that are being developed, we want to include patients who have NASH with stage 2 fibrosis or higher. We've also noted that patients who have bridging fibrosis or cirrhosis, that is, advanced fibrosis, have even higher risk than those with earlier stages of fibrosis. And these patients have significantly increased risk of developing liver decompensation and also hepatocellular carcinoma

I believe most of us know the answer to this next question, but it's still important to discuss. We have historically used liver biopsy to diagnose fibrosis, but why might we not consider other strategies? If we think 1 billion people worldwide have non-alcoholic fatty liver disease, we cannot utilize liver biopsy to risk stratify them so it becomes natural for us to identify pathways where we can risk stratify individuals with minimal risk.

For liver biopsy assessment in a hepatologist clinic, the reference standard still is a liver biopsy evaluation. The benefits of that approach is we can have a specific diagnosis, but we only entertain that in a select group of patients where we see there's a clear indication for doing a liver biopsy. The limitation of liver biopsy assessment is that there is potential risk for sampling variability and when a biopsy is read, there might be intra- and inter-observer reader variability as well. Now, you may have some inaccuracies in assessing fibrosis as well. The procedure may itself be costly but it's an invasive procedure and risk include pain, infection, bleeding and making a hole to the organs around the liver and very, very rarely it can also lead to death. Therefore, for patients and also clinicians, we want to really identify our patients who are at increased risk without doing a liver biopsy and try to identify noninvasive ways, especially for those who have minimal risk for progressive liver disease.

Now you may be asking how best can we identify those who need to be treated without a liver biopsy? One of the approaches that we've discovered or developed over time and validated is a sequential approach, and I'll give you a few examples of those and we'll discuss the role of noninvasive strategies, serum-based biomarkers, and also imaging-based and elastography-based biomarkers as well. If you're listening and are watching this discussion, you are probably an endocrinologist, gastroenterologist, or hepatologists, right? Traditionally, NAFLD has been diagnosed and managed by hepatologists, but with the recent availability of many of these noninvasive tests that we are about to discuss, gastroenterologists, endocrinologists, obesity medicine specialists, and primary care can all attain knowledge to be able to manage these patients and make these diagnoses accurately.

To acknowledge this, the American Gastroenterology Association in 2021 published a call to action encouraging a unified international public health response to non-alcoholic fatty liver disease and we are going to discuss that pathway as well. More recently, American Association of Clinical Endocrinology worked with American Association for Study of Liver Disease to come up with their guidance statement. And more recently, the AASLD's NASH Taskforce developed a group of experts to update our guidance, and this was recently discussed at the AASLD liver meetings in Washington, DC.

Let's take a look at the AGA clinical care pathway. I've modified it a bit to be more inclusive so we have additional tests that if you were to have those tests, you could understand how they could be utilized in your clinical practice. Now, the first factor to assess is the risk of having metabolic syndrome, how many risk factors you have, 2 or more metabolic risk factors, presence of type 2 diabetes, and age is also important in terms of risk for fibrosis. And then you might find steatosis on imaging, or you might have a patient who has elevated ALT or AST levels. If you see any of this, this might be a patient you might want to assess how much alcohol they consume, and if you have a complete blood count or a complete metabolic profile that includes a liver function test, you might be able to then assess, noninvasively, the risk for fibrosis.

One of the tests that is recommended is FIB-4. And what FIB-4 includes is a clinical prediction rule that includes age of the patient, serum AST levels, serum ALT levels, and a platelet count. And these are routinely available tests on complete blood count and complete metabolic profile. Based upon a totality of evidence, if the FIB-4 is below 1.3, these patients have low risk for having advanced fibrosis. If the FIB-4 is between 1.3 and 2.67, these are patients who are indeterminate risk for advanced fibrosis, and they would need a second test. If the FIB-4 is 2.67 or higher, these patients may be considered for referral to a liver doctor because the likelihood of having advanced fibrosis increases in this population. But using this approach, you could risk stratify all the patient and 60% to 70% would be in the milder category for FIB-4 and therefore, may not need that frequent and evaluation for disease progression. And those would be classified as low risk. Once you've done a liver stiffness assessment in a patient that has a FIB-4 between 1.3 and 2.67, we can further stratify a patient. If liver stiffness on FibroScan is 8 kilopascal or less, that patient has a low risk. Those between 8 and 12 kilopascals would be, again, an intermediate risk. And those were 12 kilopascal or higher would be considered high risk for advanced fibrosis and would be seen by an hepatologist. Now, if you had MR elastography available, which is 1 of the more accurate tests for detection of fibrosis, you have certain cut points that I have alluded to. If the MR elastography is less than 2.5 kilopascal, that patient has a low risk for having advanced fibrosis and that patient could be monitored in primary care setting. And if you were to do serum-based test that will be an enhanced liver fibrosis panel that is below 7.7, the risk of having significant fibrosis is pretty low, so those patients can be managed and could be followed every 2 to 3 years for seeing a change in their FIB-4 over time. Those who are in the middle with the indeterminate risk might need additional investigations and may be referred to a hepatologist for further evaluation and might even undergo a liver histology evaluation.

How do we detect or diagnose NAFLD? The traditional assessment is on a liver biopsy, but more commonly in your practice you might do an ultrasound that's routinely utilized. It's important to understand the limitations of ultrasound, in that it may not uncover presence of steatosis, especially if it is mild. If you have 5% to 10% or up to 15% fat in the liver, ultrasound may not be able to pick that up. So, it's not sensitive and has a low negative predictive value. CT scan is also not favored. Now on FibroScan machine, we have a test that is available called control attenuation parameter; 288 decibels per minute corresponds to an MRI-PDFF of 5% or higher, and this could be utilized for diagnosis of fatty liver. MRI proton density fat fraction and MR spectroscopy are really the gold standard for fat quantification and are currently utilized in treatment trial as well as in large epidemiologic studies. We're also developing ultrasound-based tests to quantify liver fat.

What about imaging biomarkers of fibrosis? As opposed to liver fat where we have a biomarker to quantify intrahepatic triglyceride content on MR spectroscopy, fibrosis assessment, there is no clear molecular signature. So, the detection of fibrosis is indirectly, using indirect methods. One of the indirect methods that we utilize is stiffness, how stiff the liver is, and related to that we translate into how fibrotic it might be. The idea is greater the degree of fibrosis, the liver becomes harder.

Let me ask you this question. Are you confident you know how to use the FIB-4 in your routine clinical practice? Here's what you need to know about it. And you can actually calculate it if you just do an [online search] for FIB-4, you'll be able to get to a medical calculator and you can plug in these numbers when you are sitting in front of the patient in the clinic and be able to get that number and record in your notes. It includes age, ALT, AST, and platelet count. If it is below 1.3, low risk. If it is 2.67 or higher risk. And those in the middle would be classified as indeterminate risk.

Another question. Do you know when to use a second-line test such as enhanced liver fibrosis panel? Here's what you need to know about using the ELF test. The ELF test is a proprietary blood test that gives you information on liver disease severity and prognostication. It incorporates 3 serum biomarkers including hyaluronic acid, PIIINP, and TIMP-1. And this gives you a good assessment of the risk of progression for a particular patient with a liver disease. When we use ELF test to predict fibrosis, what is the cut point that predicts high risk of progression to cirrhosis among those who have bridging fibrosis? ELF of 8.8, ELF of 9.8 or higher, ELF of 11.3 or higher, or ELF of 14 or higher? For those who answered ELF greater than 9.8, you are correct. Here I'm showing you data that you could utilize these tests based upon the cut points you receive: 7.7 or below, low risk for fibrosis; 9.8 or higher is associated with high risk for progression to cirrhosis. In patient with cirrhosis, 11.3 or higher is associated with high risk for decompensation over the next 2 to 3 years. And this is how I will utilize these tests in my practice. Here I'm showing you data that those who are bridging fibrosis, if they had an ELF of 9.8 or higher, over the next 2 years, they're higher risk of developing progression to cirrhosis compared to those who had ELF below 9.8. Among patients with cirrhosis and higher ELF, above 11.3 or higher is associated with greater risk of hepatic decompensation. So, this test might be utilized even in the setting of cirrhosis.

In addition to ELF test, you may have heard of FibroScan. In fact, many primary care specialists may be familiar with a FibroScan. So how is it different than ELF and when should it be used? Well, FibroScan has a modality called vibration-controlled transient elastography. And in this particular test we try to assess the elastography waves and assess the stiffness of the liver. This gives an idea of the fibrosis within the liver. There are other modalities or ultrasound that also available such as shear wave elastography, ARFI and MR elastography. And we'll discuss FibroScan as well as MR elastography in the next few minutes. This is showing you data on liver stiffness on FibroScan that higher the liver stiffness, greater the risk of liver-related morbidity and mortality and overall survival in patients with NAFLD. Now, this tells us that if the liver stiffness is 12 kilopascal, these patients would be at higher risk for developing hepatic decompensation over the next 10 years of follow up.

This is data on MR elastography showing that a cut point of 3.63 kilopascal in patients with NAFLD is associated with 92% accuracy for detection of stage 3 and stage 4 fibrosis.

In the first half of 2022, the American Association of Clinical Endocrinologists published an evidence-based guideline for the diagnosis and management of NAFLD and worked with the American Association for Study of Liver Disease. We'll focus on some of the recommendations for diagnosis of NAFLD in adults from that organization. These are pretty consistent with what we saw in the AGA call to action because many of the experts served in both the panels. It's really important that we all work together to identify those patients, particularly those who have metabolic syndrome, those who have 2 or 3 features of metabolic syndrome, have obesity, prediabetes or type 2 diabetes. They may be candidates for assessing risk for their liver disease and risk for fibrosis. And we should try to risk stratify them using FIB-4 followed by something else if needed, based upon the FIB-4-based risk stratification that we previously discussed.

And now more recently, at the American Association for Study of Liver Disease, we discussed the latest guidance for 2022 that were discussed for non-alcoholic fatty liver disease. In this guidance, we talked about a few things that are new and have been updated since 2018 guidance. Some of the features that came along in that guidance include those who have type 2 diabetes have a very high risk for having advanced fibrosis and those patients should be screened for advanced fibrosis. In the new AASLD practice guidance, we also came out with a recommendation that those with family history of advanced fibrosis, particularly the first-degree relative, should be screened for advanced fibrosis. And the modalities to screen for advanced fibrosis include FIB-4 assessment plus a list elastography assessment that includes a FibroScan, could include MR elastography, could include even other modalities related to magnetic resonance imaging.

I hope this presentation has increased your confidence in using noninvasive tests for liver fibrosis in your patients with chronic liver disease, particularly non-alcoholic fatty liver disease. The key takeaways here are the noninvasive assessment is taking the center stage in risk stratification. If you assess the number 1 risk factor is when the patient comes in with metabolic syndrome or type 2 diabetes, patient has obesity. These patients may have increased risk for having NAFLD and also advanced fibrosis related to NAFLD. In these patients think about FIB-4 assessment first. You may already have those data available based upon a complete blood count or a complete metabolic profile done for the patient. Try to calculate FIB-4 for those patients. If the FIB-4 is below 1.3, these individuals are at lower risk. Those that have a FIB-4 or 1.3 or higher, this is where you're going to do the second test, and that could be in most circumstances, either a FibroScan or an enhanced liver fibrosis panel, a blood-based test. Based upon the results of those tests, you would be able to identify if your patient should be referred to a hepatologist or not. If you see a FIB-4 of 2.67 or higher, that patient, I would recommend that be seen by a hepatologist at a higher priority. And for other patients you have time to further risk stratify them. Now, what if the patient has a FIB-4 below 1.3? You could keep reassessing them with a FIB-4 every 2 to 3 years, and this may provide you a good framework of how to risk manage your patient. Now, it's important that all patients with non-alcoholic fatty liver disease receive some sort of lifestyle intervention and lifestyle guidance in terms of maintaining their body weight, losing weight if they're overweight or obese, and if they have type 2 diabetes, then managing that well as well. With that, we will be able to provide a complete risk stratification for our patients who are suffering from type 2 diabetes and metabolic syndrome, who may be at increased risk for developing advanced fibrosis.

Thank you for participating in this activity. Please continue on to answer the questions that follow and complete the evaluation.

This transcript has not been copyedited.

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