FEMALE SPEAKER: Welcome to Mayo Clinic COVID-19, Expert Insights and Strategies. The following activity is supported in part by an independent medical education grant from Pfizer Inc and is in accordance with ACCME guidelines.

AMANDA CHANEY: Hello, my name is Amanda Chaney, and I am bringing you today a lecture as part of the COVID-19 Expert Lecture Series. We're going to talk today about NAFLD and NASH and what the difference is between those diagnoses are, as well as a little bit about COVID-19 and how to approach the patient who has fatty liver disease with COVID-19.

Here are my disclosures. So we have a few objectives to talk about today with this talk. We're going to differentiate between NAFLD and NASH. We're going to state two reasons why a liver biopsy would be needed for the patient with fatty liver disease. We're going to discuss three non-pharmacological treatments in the treatment of fatty liver disease as well as some current investigational pharmacology regimens.

But first of all, we need to talk a little bit about the background of NASH and NAFLD. And we know for sure that it is definitely underestimated. We believe that many more patients have fatty liver disease than what is discussed in the literature. We estimate that there's a global prevalence of about 25%. Patients with metabolic syndrome tend to have a higher prevalence of fatty liver disease. And we know that there is an increased mortality risk in the patient with fatty liver disease, specifically with coronary artery event or cardiovascular disease.

It's the third most common cause of hepatocellular carcinoma. And NASH currently is the second most common cause for a liver transplant or an indication for a liver transplant. Currently our numbers reflect a viral hepatitis being the number one cause, Hepatitis C, but soon we believe that because of fatty liver disease becoming more common and Hepatitis C having such great treatment regimens that NASH-related cirrhosis is quickly going to taking over for that number one spot. We know that obesity is a predictor of NASH-related cirrhosis as well.

When we think of NAFLD, when we say that term, it means Non-Alcoholic Fatty Liver Disease, and really, all that means is that there's evidence hepatic steatosis or fat in the liver cells. There's lack of secondary causes of why there would be fat in the cells, and there's no significant alcohol consumption or coexisting liver disease as a cause for this to happen.

We know there's several comorbid conditions in association with fatty liver disease, and those include dyslipidemia, diabetes mellitus, obesity, polycystic ovarian disease. Metabolic syndrome is common as well. And when we think of NAFLD, we need to think of it as a spectrum of disease. So we have Non-Alcoholic Fatty Liver. So that's just like the big umbrella of disease.

Then we can break that down into the hepatic steatosis where there's fat in the liver cells. Gradually, if that goes on for a prolonged amount of time, inflammation occurs in that. And so that inflammation is called non-alcoholic steatohepatitis. That's the inflammation piece. And then eventually, cellular changes occur and can cause fibrosis and then cirrhosis and sometimes hepatocellular carcinoma.

The pathophysiology is not well understood. It is complex, but there is thought to be believed that there is an insulin resistance problem. So insulin receptors become less responsive to insulin in the cell and blood sugars in the cells. And as a result, the liver responds by increasing fat into those cells.

In addition, fat going out of the cells becomes impaired, and there's decreased fatty acid oxidation. And as a result, these fat globules form in the cells, and they just enlarge and enlarge. Later on, there's a second hit, and cytokines are released and inflammation occurs, which leads more to oxidative stress and cellular death, which then causes those cellular and structural changes leading to fibrosis and cirrhosis.

This is a really good depiction of the fat globules in the cells, the steatosis as I mentioned. And these fat droplets form and grow within the hepatocytes. The liver becomes enlarged. It's soft. It's greasy. It's yellow. The cells become fragile and unstable. And as a result, the cytokines are released. Free radicals are released.

Then this reaction occurs leading to mitochondrial death and leading to cellular death as inflammation occurs. And so this inflammation plus fat in the liver cells equals steatohepatitis. And it can be with or without alcohol. So if it's because of alcohol, then it's alcohol steatohepatitis. If alcohol can't be blamed, then it would be non-alcoholic steatohepatitis. Chronic NASH leads to fibrotic tissue then leads to structural design impairment. And so then fibrosis develops as well as cirrhosis.

We believe that there is a dietary component to this. With high consumption of cholesterol and/or sugar, it causes more fat to be deposited into the liver. This can cause more inflammation and injury. And then we know that there's insulin resistance problems with patients with diabetes.

And so that can cause further injury as well as if a patient has hypertriglyceridemia or hyperlipidemia that cholesterol is high and elevated within the plasma and in the bloodstream. And so with more of that occurring, there can be more of the fat being available for consumption in the liver. All of this causes more injury and inflammation. It's good to point out, though and we should point out several times in this talk that it can be reversed with diet, exercise, and good blood glucose control.

So what do you do at first? So with your initial evaluation, you're going to exclude other causes. So you're going to get some laboratory testing, ruling out any autoimmune components, ruling out any other biliary issues or viral hepatitis that could have caused liver injury. You want to understand if there are any other presence of other comorbidities, so any other issues of hypertension, metabolic disease, autoimmune disease anywhere else in the body.

Liver biopsy is the gold standard for diagnosis, but it does come at a cost, and it does have its risks with the procedure, such as bleeding and infection and bowel perforation. And so definitely this should be done at a center where they do a lot of them and there is an expert who does it.

Some non-invasive ways to figure out if a patient possibly could have fatty liver disease or a few calculations-- one is the NFS. One is the FIB-4. There's additional imaging, and then there's a fairly new school of thought about cytokeratin-18 fragments, again, being studied, not anything that's readily available in our current state in 2020.

So the first stop point as far as what imaging studies to get, you would want to get an ultrasound at first if you suspect this happening with your patient. And any of these imaging studies can pick up fat in the liver cells. So an ultrasound, CT scan, MRI can see fatty infiltrates in the liver.

You also want to know if there's a degree of fibrosis. So the degree of fibrosis should be evaluated, and how do we do that? Well, there's a few laboratory testing scores that you can look into such as a NAFLD Fibrosis Score, the FIB-4, the AST-Platelet Ratio, but then, FibroScan elastography is another great way to do that we'll look at. What's really important for us to know is a higher degree of fibrosis equates to poorer outcomes. So we definitely want to know earlier if we can and know how to reverse the issues going on with the insulin resistance and the fat deposition in the liver.

Let's talk a little about elastography. So FibroScan is becoming more and more popular. It's shear wave through the liver. More stuff equals more fibrosis. It is really good in determining the degree of fibrosis that's an F3, F4, which is advanced fibrosis before cirrhosis. And so the score on that would be 8 to 12 kPa or greater. Magnetic resonance can let us know fibrosis scores, but it is expensive and not easily as available as the FibroScan would be.

But there are some complications of fatty liver disease, and the most important and independent risk factor is for cardiovascular disease. So if a patient has fatty liver disease, they should also be evaluated for cardiovascular disease. So number one, looking at comorbidities such as hypertension, hypertriglyceridemia, hypercholesterolemia, looking for any reason for cardiac disease.

And so stress testing may be necessary if a patient has chest pain or symptoms of cardiovascular disease. And if cardiac catheterization is indicated based on stress test findings, then definitely that should be done, and you should go ahead and proceed with that.

Dyslipidemia-- you would treat dyslipidemia just as you would anybody in the general population. I do get frequent consults about patients who have liver disease for one reason or another and should they continue with their statin, and the answer is yes please. Fibrates are important and good for patients with Hyper triglyceridemia. Hypertension-- goals as per the general population. And we can use things like ACE inhibitors or ARBs. Those are good for this patient population.

A few things we need to think about is obstructive sleep apnea. So if a patient has comorbidities significant for obesity, then we would want to have them go for a sleep study to understand if they are having any sort of sleep apnea as well as getting them a CPAP machine if one is needed. We also want to think about chronic kidney disease, especially in a patient who has had longstanding diabetes. They could have kidney injury, and we would definitely want to make sure that they have that identified and treated appropriately.

So what about fatty liver and COVID? So this was a paper that was published earlier this year in 2020. And it talks quite a bit about patients with liver disease during the COVID-19 pandemic. One thing that we really have to think about is there has been significantly noted in the literature that patients who have metabolic syndrome, who have obesity, who have hypertension, metabolic syndrome, these patients when they do have COVID-19 are more at risk for a severe infection. And so we have to be aware of that, and we have to make sure that if it is identified, then we promptly get those patients treatment as soon as possible.

So what are some non-pharmacologic treatments for fatty liver disease? Weight loss and lifestyle modifications are the mainstay of treatment. We want to aim for a patient to reduce calories about 500 to 1,000 per day, incorporate moderate intensity of exercise, and there have been some research studies that have shown and proven that with a 3% to 5% weight loss, their liver pathology changes and improves.

And so just with a 3% to 5% weight loss, there is shown to have improvement in steatosis. With a greater than 7% weight loss, NASH is improved. And with a greater 10% weight loss, we know that fibrosis is improved in those patients. And so to me, this is a very powerful piece of data, and I think it's important to share this with our patients, that we know that weight loss and diet and exercise and lifestyle changes can work if you do the hard work.

We want to tell them to avoid alcohol consumption. So don't add any more insult to injury. Get the diabetes under control. Make sure that there's no additional contribution to causing more fat to be in those cells. And aggressive modification of the cardiovascular disease risk factors-- so definitely controlling the diabetes, controlling the dyslipidemia, ordering the statin if indicated and they need that, and then making sure that they have a sleep study if sleep apnea is a concern as well as a CPAP machine.

So what do we do when we talk about lifestyle changes? So it's not a diet. It's something that they need to seek out for the rest of their lives. And so making sure that there's protein with every meal, a healthy portion, a big portion of vegetables and fruits. Focus on carbohydrates and ensure that they're not exceeding a certain number. They can partner with a nutritionist to actually guide them on what those numbers should be.

Set reasonable goals using the SMART goals. So making it Sustainable, making it Measurable, making it Accessible, Realistic, and Timely. So just thinking about very specific ways and small tiny goals at first. And then, as they see that that's working and that that's a positive change and that they feel better, then it will encourage them a little bit more. I always like to keep a positive focus and make sure that patients are not banging themselves up too bad about not losing weight quick enough. It's a lifestyle change, and it's a marathon. It's a journey. It's not going to happen quick with a snap of our fingers.

So one important question that I think we need to be mindful of with the patient who has obesity is can a patient with obesity have malnutrition, and the answer is yes, they can have both diagnoses at the same time. Obesity is a measurement usually by definition of BMI, and malnutrition is looking more muscle mass, looking more about quality nutrition. And so I have had many patients who are both, who have-- and the notes documented a well-nourished person, but then they have malnutrition because the quality of their nutrition is not good, and they are having significant muscle wasting, especially in the patient with liver disease.

Sarcopenia is common, and it is actually related to more poor outcomes in the post transplant setting. So that's really something we should be mindful of in this patient population. The NASH patient is most likely to be sarcopenic. And partnership with physical therapy, nutrition is really important to optimize nutrition choices as well as talk about strategic exercise to improve muscle mass and conditioning.

There are some options for surgery for a patient who is obese and has NASH, and I would consider it on a case by case basis. There are some studies out there that are doing bariatric surgery at the time of a liver transplant for a patient with NASH-related cirrhosis, and more details will be coming forth in the coming years, I think, about that.

We definitely know that bariatric surgery is effective in weight loss and decreases a patient's cardiovascular events and mortality, as well as improves their diabetes. And so just know that this option is out there and that it should be determined on a case by case basis. And a patient really needs to be ready for such a drastic lifestyle change as well.

There are several different kinds. Roux en Y is one of the earlier versions and most common. And then there's an Adjustable Band where the band is around a portion of the stomach and just limits the amount of food and liquids that a patient can take. And the Duodenal Switch is another one. Roux en Y and Duodenal Switch do have their risks of dumping syndrome and more malabsorption issues, but again, close collaboration with the surgical team and a multidisciplinary approach is definitely important if this is the route that you wish to go.

So there have been a lot of buzz in the literature and at meetings about when are we going to have a medication to treat NASH, and currently, we are not there. There is no FDA-approved medication for the treatment of NASH. Metformin has been studied, but is not recommended as a treatment for NASH.

There are some thiazides that improve histology for NASH-proven cirrhosis, and then, plus or minus whether or not they have diabetes or not, but there is no for sure recommendation or practice guideline that supports that as of yet. More studies are needed on these other medications, but again, they've been studied, but they just haven't been approved yet for this purpose yet. So again, the mainstay of treatment is lifestyle changes, and there is no medication right now to treat NASH.

Other things in the literature, Vitamin E is prescribed sometimes for patients who do not have diabetes but have NASH-proven cirrhosis or fibrosis. It's not recommended in other groups. So it's not recommended in patients who are diabetic. And then, Urso is not recommended. It's been studied, but again, not It didn't have a really proven, exceptional outcome for those patients. And then, Omega-3 fatty acids are not recommended for NASH or NAFLD, but you can consider it in a patient who has high triglycerides along with fatty liver.

So the patient with NASH-related cirrhosis, we do have to be mindful that their risk of cardiovascular disease and cardiovascular events is higher. So knowing that is helpful when determining your next steps in managing this patient long term. If the patient has cirrhosis, they should be screened per practice guidelines for esophageal varices as well as for hepatocellular carcinoma.

The routine screening for hepatocellular carcinoma is every six months by either CT with contrast or MRI. And then esophageal varices screening with EGD is recommended every six to twelve months. If there is banding, then possibly more often if those are found-- varices are found, and they needed to be treated.

Routine repeat liver biopsy is not really recommended. They have cirrhosis. There's not really a point in getting another biopsy to show that they have cirrhosis again. And then, we need to determine at this stage, we know the patient has cirrhosis, so are they compensated and they have no evidence of ascites or any other complications of cirrhosis, or have they moved into a decompensated state, and if that's true, then they need an evaluation for a liver transplant at a transplant center. If they also have developed a notable HCC or hepatocellular carcinoma, then they would need to go to a transplant center for evaluation at that point as well.

In a post-transplant setting, we know that it does worsen metabolic syndrome, especially for patients who already have that initially. Immunosuppressants such as tacrolimus as well as steroids can worsen triglycerides. It can worsen cholesterol. It can worsen hypertension as well as glucose levels. And so we need to be aware of that in the post-transplant setting and treat those promptly and [AUDIO OUT].

Other complications and challenges with NASH patients who have already, because of their complications of cirrhosis, they have hepatorenal syndrome. This possibly could be worsened in a patient with fatty liver disease because of co-existing renal damage maybe because of diabetes. Or a patient who already has hepatopulmonary syndrome, if they have on top of that obstructive sleep apnea or cardiovascular disease, it could contribute more to their risk of hypoxia and make that worse.

For the patient who has ascites, there could be some challenges with getting a good sample for a paracentesis due to the adiposity of the truncal obesity that could lead to some challenges. And then, patient with portal hypertension, that is a little bit worse in the patient with obesity. And so having all of these notations in your mind and considerations is important when caring for the patient with fatty liver disease.

A patient with obesity and diabetes, their risk of cancer increases even in the absence of cirrhosis. Just because of those two co-existing prognoses, that risk for cancer does go up. So again, that imaging every six months is really important to make sure that they do not have an HCC, or if they do, we identify quickly and treat it accordingly.

And then, the patient who has ongoing use of alcohol, whether it's social or even just a drink every now and then, that does increase their risk for HCC as well, so another key component to be aware of. We mentioned earlier to treat hypertension, treat hyperlipidemia and high cholesterol just as if you would the general population. So please make sure that you tell your colleagues to treat that accordingly.

And then the patient with fatty liver disease and who is a pediatric patient, definitely the same. It's the same treatment evaluation. It's the same as with adults. So test for other causes. There's not enough evidence to support routine screening. So just because a mom or dad has fatty liver disease or metabolic syndrome, it doesn't necessarily mean that we need to screen their children for that. There just isn't enough literature out there to back that up.

Liver biopsy would be indicated if the diagnosis is unclear, prior to start of any hepatotoxic medication, specifically, like I'm thinking for acne or anything like that, and then potential for multiple causes of liver disease. So you would want to know them for biopsy.

There's unique characteristics seen on pathology with this patient population, and having that biopsy done at a pediatric transplant center would probably be your best idea. Again, the mainstay of treatment is lifestyle modifications. Again, there's no medication to treat fatty liver at this time.

So what's on the horizon? So the goal of the new NASH treatments or what we hope that we can accomplish in the next few years is that these treatments provide histological improvements. They improve fibrosis. And the new medications are like once a day, one pill once a day with minimal side effects. And so that would be a dream. That would be fantastic to be able to set it up that way. There are some medications that are in phase 3 trials, but again, nothing is approved as of yet.

So in conclusion, I just want to remind you that fatty liver disease is a broad spectrum of disease. Other causes of liver disease should be ruled out. Many patients are asymptomatic and are walking around just doing fine. Sometimes we don't even know a patient has fatty liver disease until they have an ultrasound or abdominal imaging for another reason, and incidentally, we find fatty liver disease.

There is a strong association between fatty liver disease and cardiovascular disease. So please be aware of that and treat other risk factors for cardiovascular disease appropriately. Lifestyle changes are the mainstay of treatment. If there are any signs of decompensated cirrhosis, the patient should be referred to a transplant center for liver transplant evaluation. And we know that the risk factor for hepatocellular carcinoma is increased with alcohol consumption no matter how little bit of it is and with fatty liver disease.

That concludes this presentation, and here's my contact information. If you any questions, feel free to contact me any time. Email is usually the best way to get a hold of me. And I hope this was really helpful for you. Thank you so much.