Diagnosing and Managing NAFLD and NASH

In this video, three experts in gastroenterology and hepatology—Alan Bonder, MD, Gordon Jiang, MD, and Hirsh Trivedi, MD—discuss the diagnosis and management of nonalcoholic fatty liver disease and nonalcoholic steatohepatosis in the primary care and specialty settings.

Alan Bonder, MD, is an assistant professor of medicine at Harvard Medical School and medical director of liver transplantation at Beth Israel Deaconess Medical Center in Boston, Massachusetts.

Gordon Jiang, MD, PhD, is gastroenterologist at Beth Israel Deaconess Medical Center and an assistant professor of medicine at Harvard Medical School.

Hirsh Trivedi, MD, is a 3rd-year gastroenterology and hepatology fellow at Beth Israel Deaconess Medical Center/Harvard Medical School.

Transcript:

Dr. Alan Bonder: Welcome to Gastroenterology Learning Network. My name is Alan Bonder. I'm one of the transplant hepatologists at Beth Israel Deaconess Medical Center, and I will be moderating today's discussion on the diagnosis of management of NASH in the primary care setting and hepatology setting.

I'm joined by my colleagues from Beth Israel, Dr. Hirsh Trivedi and Dr. Gordon Jiang. Again, I want to thank you both for joining me in this video and in these discussions. I want to start with Dr. Trivedi first.

Based on your research, can you comment on what the primary care provider needs to know about NASH, who should be screened, and how do we stage, or what are the people who we are concerned, and who should be referred to a transplant hepatology or a hepatology department?

Dr. Hirsh Trivedi:  Sure. First off, I just wanted to thank the Learning Network and Dr. Bonder for the introduction, and thank you for having me here today. Nonalcoholic fatty liver disease is a growing disease with an increasing prevalence that is in parallel to a lot of other conditions that we commonly see in the primary care clinic.

Those include type 2 diabetes mellitus, as well as obesity and metabolic syndrome. It is a spectrum of disease that ranges from simple steatosis, which is a relatively benign disorder that, on the more severe end of the spectrum, can turn into nonalcoholic steatohepatitis, with possible features of advanced fibrosis or cirrhosis.

That disease etiology tends to be more progressive in nature, and it causes a lot of complications. Not just cardiovascular mortality, but also liver-related mortality, such as hepatocellular carcinoma and liver decompensation, which can be in the form of encephalopathy, ascites, or hepatorenal syndrome.

It's very important to be able to differentiate these patients who have simple steatosis and a relatively benign course, from those who have more advanced disease, and more advanced liver disease, who can go on to develop complications.

We know that NAFLD is profoundly underdiagnosed in the community itself. A lot of the reason behind that is because the traditional liver function tests that we use are unreliable in risk-stratifying these patients.

We need better noninvasive tests to help risk stratify patients in the community. There has been a lot of research going on currently with such noninvasive tests. One of the serologic tests that are easily available to primary care physicians includes the Fibrosis-4 Index score, which just constitutes the liver function test as well as age and platelet count.

That can be easily calculated in any primary care clinic. If anyone has any evidence of fatty liver disease, or if there's a patient who is in a high-risk category, such as those with metabolic syndrome or type 2 diabetes, you can calculate a quick FIB-4 Index, which you can google online and find it.

That can help you risk-stratify whether the patient has a benign course of disease, with a low fibrosis level, and, therefore, can continue to be monitored in the primary care clinic, or whether the patient needs further noninvasive assessment and surveillance with a specialty hepatologist.

I recommend using that in the primary care clinic as the first step.

Dr. Bonder: Is there a role of the FibroScan in the primary care setting, Hirsh?

Dr. Trivedi: Yes. FibroScan is a great test. Another name for FibroScan is transient elastography. It has a very high negative predictive value at certain cutoff levels. If we have a low score, there's a very low chance of these patients having advanced fibrosis.

The issue is that the accessibility to FibroScan is variable, and it's most of the time in academic centers or large institutions. Access may be variable in the community setting, where a lot of our underdiagnosed NAFLD patients reside.

Yes, if it is available, I highly recommend its use. You can consider it even before FIB-4 score, but if access is varied or you have limited accessibility to it, then you can consider FIB-4 as an alternative measure.

Dr. Bonder: Just to mention, or summarizing everything that you said, if you are in the primary care settings, and you have a patient with diabetes, does that patient need to be screened for a fatty liver?

Dr. Trivedi: Yes. I would screen that patient with a FIB-4 score, and you should evaluate that patient for fatty liver disease. I completely, 100% agree with that.

Dr. Bonder: Then in the primary care setting, what would you recommend to that patient who is found to have abnormal liver tests and a fatty liver? Would you say, "Based on your FIB-4, you have low fibrosis, and you need to lose weight, exercise"?

Do you need any specific treatment? Can the primary cares recommend still treating your cholesterol? What would you say to that primary care that needs to manage that patient?

Dr. Trivedi: We know the negative predictive value of the FIB-4 score is pretty good. Therefore, I think we can rely on a low FIB-4 score in the primary care setting in that patient who's diabetic and who might have other signs of fatty liver disease.

I would recommend them repeating the FIB-4 score every year while they're instituting weight loss measures and treating the underlying metabolic syndrome or the type 2 diabetes.

Dr. Bonder: Now, moving on, and that patient has an elevated FIB-4, and then comes to see Dr. Jiang in the liver clinic. Then Dr. Jiang is meeting this person for the first time. What are the key features, or what are the things that you will look as a first encounter to a patient who has an elevated FIB-4?

Is this patient someone that you will assess with just a FibroScan? Does this patient need a liver biopsy? How do you stratify these patients? How do know if this patient is at risk for progressing to cirrhosis, or is at risk for progressing to more advanced liver disease?

Dr. Gordon Jiang: Also, I would like to echo that I thank you for the opportunity to be here, to have this very interesting discussion. It's a very, very common problem that we see a lot of patients referred to us because of either finding fatty liver disease or having features of, concern for progression of the disease toward a more robust state.

The question is how do we accurately stage the patient and provide some guidance? I think, as a hepatologist, the thing that I'm always thinking about is whether this patient will have the chance of developing cirrhosis from the nonalcoholic fatty liver disease.

From the liver perspective, what matters is whether this patient will end up having cirrhosis. There are a lot of other implications of having fatty liver disease and having comorbidities from metabolic syndrome, but as studies have over and over shown, that the liver-related and morbidity and the mortality is associated with fibrosis, is associated with development of cirrhosis.

From the biology perspective, if we think about the epidemiology, there is about 20% to 30% of the population in the United States have fatty liver disease, but only 5% of them end up having cirrhosis.

This means that 95% of the patients with nonalcoholic fatty liver disease, they don't end up having cirrhosis. There are some things unique about these patients that eventually develop cirrhosis. The way I look at this, there are two type of things will be driving the disease toward cirrhosis.

One is genetics. As we more and more understand, there is a very, very strong genetic component driving people with nonalcoholic fatty liver disease toward cirrhosis. Unfortunately, genetic testing is not part of the standard of care yet.

I think this may change in the future, but we don't have the luxury of checking the genetics. There are signals that I can pick up from the history, from the physical exam, from the clinical information to estimate that this patient may have an increased genetic predisposition, such as family history.

If the patient has a strong family history of cirrhosis, especially cryptogenic cirrhosis, you will have to think about genetic features. For example, if some patient has a very strong family history of cryptogenic cirrhosis or fatty liver-related cirrhosis, then you should worry about a genetic component driving the disease.

Or if somebody doesn't have a lot of comorbidities of metabolic syndrome, you will be thinking about there may be a strong genetic component there. Ethnicity may play a role. We know that fatty. liver disease and the progression of fatty liver disease is more common among Hispanics, compared to African Americans, for instance.

The second part of the pathogenic driving force is insulin resistance. If somebody has a very strong component of diabetes, of morbid obesity, you would be worried about a rapid progression. This is the information that, without much testing, you would be worrying about the rapid progression of the disease.

The second part of my evaluation, I will be thinking about where that patient is on the progression of nonalcoholic fatty liver disease. That comes down to the fibrosis.

It will start with a noninvasive testing, like transient elastography. It can be FibroScan, or it can be ultrasound-based transient elastography, or it can be a MRE elastography, depending on what modality is available to you. Of course, you always have the option of doing a liver biopsy.

As part of the evaluation, I will also make sure that, if the patient does not have any coexisting chronic liver disease, that it's very common for a nonalcoholic fatty liver disease patient to often also have viral hepatitis.

Dr. Bonder: It could be triggers from a FibroScan, so from that ultrasound elastography and MRE elastography, that would say to you, "OK, this patient is not at increased risk. This patient has some risk, but I'm OK watching him for a little bit."

Or, "This is a patient who definitely has this risk, and I'm going to start screening him for complications of liver disease." How would you think about those kind of ways to try to put your patients in different categories to make sure that you follow them properly?

For example, my question is, if a patient who Dr. Trivedi sends you from the primary care with a low FIB-4, and that's confirmed by low FibroScan, is there any concern that this patient could progress to a more advanced liver disease in 2 or 3, 5 years, and do those patients need to be followed in the liver clinic closely, or can this patient be followed just in a primary care setting?

Dr. Jiang: There are two components you have to think about. One is where the patient is. Where is the current stage of fibrosis? The second component is how fast this patient can be progressing. The other component that comes into play is the age.

For instance, if you have an elderly patient coming to you with a mild stage of estimated fibrosis, this patient probably does not have a huge risk factors of progressing into cirrhosis, because he's probably already at age 70, 80.

For a young patient to come in at age 20, 30, and has a moderate fibrosis, or have comorbidities, you will be more concerned. I would more aggressive in terms of accurately measuring the fibrosis.

Dr. Bonder: Are there any triggers that will say, "OK, based on my noninvasive testing, this patient to be better accurately staged, that we need a liver biopsy"? What are those patients that you would recommend saying, "Really, I need to do more invasive testing to make sure that I know where they are and where they're going to"?

Dr. Jiang: I will offer liver biopsy in two scenarios. One is that if there is any concern of competing diagnosis, I will offer liver biopsy. Secondly, if the patient has evidence, based on noninvasive testing, has stage 2 of advanced fibrosis, I will consider liver biopsy.

Translating to a FibroScan score, it would be a score of 8 kilopascal. That will be my trigger point. Of course, this is a decision that will be discussed with the patient when we have to discuss the pros and cons of taking a liver biopsy.

Dr. Bonder: I will say what's the percentage of your practice that you actually will end up going to a liver biopsy?

Dr. Jiang: This is a little bit of bias to the situation, because every practice will be different. In our liver center, we have an active surveillance program in the primary care communities. We get a lot of referral of patients with already-established concerns for fibrosis based on noninvasive testing, either FIB-4 or FibroScan results.

I end up doing a lot liver biopsies because of the patient is already prescreened. If a different practice, that it's less strictly featured, you may have a lower prevalence of doing liver biopsy.

Dr. Bonder: Let me just shift back to Dr. Trivedi. How would you recommend, a patient was sent to Dr. Jiang in the liver clinic. He actually is telling you that he does have an increased risk. His kilopascals in his ultrasound elastography was not too high, and is he coming back to you.

What would you say to that patient? What would you say to that primary care? How would you manage them for the future, or how would you prevent that NASH progressing to really worsening liver disease?

Dr. Trivedi: The noninvasive tests really tell you a lot, whether you're in the primary care or in the specialty clinic. If you have concordance of the 2 different noninvasive tests, you're obviously more confident in terms of accurate fibrosis assessment of your patient.

If you have an intermediate or higher-level score on either the FIB-4 or the FibroScan, your positive predictive value isn't as good. You have to be a little bit more wary in this patient. Like Dr. Jiang said, you have to take other characteristics, clinical and genetic characteristics, into the whole context of the picture when you're treating that individual patient to determine what is the best next strategy.

One possible way is, if they did have the liver biopsy, if it's just simple steatosis, for example, and you can ask the primary care physician to monitor their labs, FIB-4 every 6 to 12 months, while instituting these weight loss therapies.

Of course, if their FIB-4 were to change with repeated testing over the course of the next couple of years, I would then recommend a repeat referral to the hepatologist for further surveillance.

If we deem the patient high-risk to begin with, with high-risk noninvasive testing, and/or high-risk fibrosis on biopsy specimen, then we would want to see these patients continually in the liver clinic with routine HCC surveillance strategies, with ultrasound and/or AFP assessment every 6 months, along with assessing them for esophageal varices to prevent further decompensation down the line, given their inherently increased risk.

Dr. Bonder: Dr. Jiang, from a hepatology standpoint, this patient has advanced fibrosis, has advanced liver disease. What are the recommendations from, I would say, a liver standpoint and a nonliver standpoint to treat these cases?

I think Dr. Trivedi went a little bit about the screenings and how do we advise for them, how to take care of their liver disease. How do we treat that patient with NASH? What can we offer them? One other tip, what I'll say common question that comes up in our clinics, is can we treat these patients for their hyperlipidemia? Can we use statins?

Is there something that is currently recommended from us through liver clinics to the primary care settings?

Dr. Jiang: The treatment of NASH patients with advanced fibrosis comes into several aspects. Number 1 is they're treating the potential risks of comorbidities associated with cirrhosis, as Dr. Trivedi mentioned. Screening for CCD, screening for complications from protohypertension.

The second part is to treating the underlying cause of nonalcoholic fatty liver disease. There is no FDA-approved medication specifically for NASH, as of today. Obviously, this is a heavily invested area and things can change.

Every few months, we are seeing some new results coming up from clinical trials. There may be treatments in the future, but lifestyle intervention is very, very important for patients with this diagnosis. The focus of the lifestyle intervention will be on the weight loss.

This comes from two aspects. One is exercise, which I cannot emphasize more to my patients. They have to be creative to incorporate physical activity or exercise into their daily routine. I quite often go over with them the potential things they can do.

The second part is the dietary intervention. The key aspects will be actually very similar to the management of diabetes. That is to avoid sugar, avoid a high fructose content, and decrease the amount of carbohydrates.

There are other strategies that I call assisted weight loss. Basically, weight loss with some sort of either medical or procedural assistance. Bariatric surgery is a consideration if the patient meets the criteria. Certainly, this is something that we should discuss with our patients.

Bariatric endoscopy is a rapidly-developing alternative to bariatric surgery. Sometimes, it's safer and potentially less invasive. There are also medications as well.

Back to the question of statins. This problem has been faced very commonly, because patients with nonalcoholic fatty liver disease often have mildly elevated liver enzymes.

Statins are safe in patients with nonalcoholic fatty liver disease, all the way to patients to early cirrhosis. When the patients start to develop decompensation from cirrhosis, that's the point you want to stop statins, and the risk will increase.

Statins can increase the liver enzymes in selected patients. This question has been studied, and on the liver biopsy, there is no evidence that an elevation of the enzymes in the setting of statins is associated with true liver pathology. I think this is safe, as long as the liver enzyme is within 3 units of normal.

Dr. Bonder: Then Dr. Jiang, what would you be your recommendations? How and when to send the patient, for example, bariatric surgery? You mentioned a little bit about certain cutoffs of BMI, certain cutoffs about advanced liver disease.

What in the liver clinic is your trigger or your referral point, I would say, "This patient needs to be referred to a bariatric surgery to take care of his NASH, because really, this is the only way that the patient is going to improve"?

Dr. Jiang: Currently, bariatric surgery is not offered as a treatment for NASH or NASH fibrosis yet. From a practical point of view, we still have to use the approved indication for bariatric surgery that is based on your BMI.

For patients does not have diabetes, the BMI will be 40 or above. For patients with diabetes as a main comorbidity, the BMI can be lowered to 35. In some situations, there can be discussions whether other comorbidities can be used, but this is more of a case-to-case discussion.

Dr. Bonder: One more thing. I think it's very important. As Dr. Trivedi was mentioning, the importance of screening tests in patients who already have liver disease.

I think either in the primary care settings or in the liver clinic settings, we do have to make sure that actually both hepatologists, both gastroenterologists, and both primary care physicians know to screen for complications of liver disease when they exist.

That means getting an ultrasound every 6 months and an upper endoscopy to screen for varices, properly based on their disease. That's a very important topic.

Just to wrap up and finishing, Dr. Trivedi, can you give, I will say, the most important, the bullet points that you would say to a primary care provider?

Dr. Trivedi: The first major point that I would like to express to the primary care doctors is that have a high suspicion of nonalcoholic fatty liver disease in all of your diabetics, and in a lot of your metabolic syndrome patients as well. If they don't have it yet, just be wary that they could develop it down the line if their metabolic syndrome were to progress. That's the first and foremost thing that I would highly express.

The next thing is we're still in the research phase of trying to determine what is the best and most accessible form that is reliable of testing that the primary care docs could pursue to rule this diagnosis out.

As of now, what we have is the FIB-4 and the FibroScan are very reliable. There's ongoing research to develop more reliable testing strategies that will come in hopefully near future.

Then the next point that I would like to highlight is weight loss. Weight loss, as Dr. Jiang said, actually, is very impactful. We know that even about a 5% to 10% weight loss can start reversing steatosis. Above 10% can even start reversing levels of fibrosis. Those are the main take-home points I would make.

Dr. Bonder: How about you, Dr. Jiang? What would be your closing remarks about what is the point of view from a liver standpoint that we need to send a message to a general gastroenterologist about NASH?

Dr. Jiang: As Dr. Trivedi was saying, I think the most important thing is to think about NASH. It's a very common diagnosis, but it can have very devastating consequences. A lot of your patients probably will be fine, but you don't want to miss those who will inevitably get a complication from cirrhosis.

Testing for fibrosis is very important. Testing using noninvasive methods, and if an indication is present, to send for hepatologists, for liver biopsy, or do it yourself. Once you have the established diagnosis of advanced fibrosis, then you need to be screening for complications from cirrhosis, including checking for liver cancer.

In my personal experience, I've been surprised just by giving patients the information, giving patient the knowledge, empower the patients to know that they can make a difference, and that they're going to do the lifestyle interventions. They're going to try to lose weight.

There's a lot of success stories if the patient knows the consequence of these problems. They're going to make the changes to their life. This is when I find my work is rewarding.

Dr. Bonder: Again, I wanted to thank you both, Dr. Trivedi and Dr. Jiang, for helping me and for participating in this interesting discussion. I hope those who listened have found it interesting and helpful. You can find more video resources at the Gastroenterology Learning Network. Thank you very much, and hope you're having a good day.