COMMENTARY

Cardiologists Should Be More Involved in Treating NAFLD/NASH

Seth J. Baum, MD, FACC, FAHA, FNLA, FASPC; Jay H. Shubrook, DO, FAAFP FACOFP

Disclosures

May 24, 2021

Editorial Collaboration

Medscape &

This transcript has been edited for clarity.

Seth J. Baum, MD, FACC, FAHA, FNLA, FASPC: Hi. I'm Seth Baum, a preventive cardiologist and clinical lipidologist, past president of the American Society for Preventive Cardiology, and an affiliate professor of cardiology at the Charles E. Schmidt College of Medicine at Florida Atlantic University. I'm very happy to be here today to discuss fatty liver disease and its impact on cardiovascular disease and other aspects of patient health.

Jay H. Shubrook, DO, FAAFP, FACOFP: Hi. I'm Jay Shubrook, a board-certified family physician, fellowship-trained diabetologist, and a professor at Touro University California. I'm delighted to be talking with Dr Baum about nonalcoholic fatty liver disease (NAFLD). This is a condition we've commonly seen in our practices for a long time. At least in my practice, 80% of patients who are obese and have diabetes also have some form of fatty liver disease, somewhere between NAFLD and nonalcoholic steatohepatitis (NASH).

From my primary care standpoint, I thought of fatty liver as a big, very general class of disease. We would often see patients present with elevated transaminase levels. But then with the dual epidemics of obesity and type 2 diabetes, it became so common that we grew somewhat numb to it in primary care.

We know that NAFLD and its extension into NASH are significant contributors to disease and, at least in primary care, might be the most common cause of cryptogenic cirrhosis. We're going to find these patients who were never drinkers, who have no other risk factors, yet who go on to cirrhosis. One of the things we want to talk about today is the idea that NAFLD is also a contributor to the spectrum of cardiovascular disease.

Dr Baum, what's the cardiologist's perspective on NAFLD?

Expanding Our Understanding of Fatty Liver Disease

Baum: Unfortunately, I think most cardiologists are not paying attention to fatty liver. I don't mean that in a bad way. What I'm saying is that because there is no drug to be prescribed, and the prevalence is so great, perhaps we've given up temporarily until we have therapeutics.

Just to shed some light on the prevalence, fatty liver disease spans from NAFLD (which occurs in about 25% of the global population), to NASH in which there is cell injury and inflammation in the liver, to fibrosis resulting in cirrhosis, and then possible hepatocellular carcinoma and transplant. NASH is now the number-one cause of transplant in women, and men are certainly close behind. This full spectrum represents an enormous burden of disease.

As it relates specifically to the heart, the classic phenotype is a patient with NAFLD or NASH, central obesity, high triglycerides, low HDL, a large number of apoB-100–containing lipoproteins, high atherogenic lipoprotein burden, perhaps diabetes, certainly insulin resistance, hypertension. These are all cardiovascular risk factors. Therefore, this patient that we're describing with fatty liver is also one who will ultimately develop cardiovascular disease.

The question is whether there's an independent risk for cardiovascular death among these patients, which it looks like there very well may be. So it's a big deal. I think cardiology is going to pay attention to this over the next several years, especially given that there are lots of drugs in development for this issue.

Shubrook: It sounds to me like NAFLD really should be considered as an inflammatory disease, contributing to those things that lead to cardiovascular disease. Because if we just think of it as a simple obesity problem, that returns us to what will be a not very therapeutic approach. Is it correct that there's more to this than just the fat itself?

Baum: That is correct. That's clear from the drug candidates in this area, which are being developed with one of three issues in mind (though usually some overlap): inflammation, metabolic derangements, and fibrosis. These are the mechanisms at play in a very intricate and complicated way, as it is with diabetes, with various cellular, hormonal, chemokine, and cytokine influences.

Endothelial function is affected, and oxidative stress and inflammation occur, which can affect plaque formation, plaque instability, arrhythmogenesis, etc. We could go on and on. But we must understand that all of these very complicated metabolic and other derangements have an interplay with considerable cardiovascular toxicity.

Shubrook: From the standpoint of a primary care diabetes practitioner, we commonly look at therapeutic weight loss as a cornerstone treatment. Of course, many of our patients already need that anyway, but we do counsel them that lifestyle interventions make a difference, including avoidance of alcohol and other toxins.

We also use vitamin E in people who do not have diabetes, and sometimes we use pioglitazone in people with diabetes. There may be some updated guidelines and new studies coming out in this area, but right now that's standard. I think these are somewhat atypical treatments from a cardiology standpoint when treating your patients with NAFLD, right?

Baum: In regard to pioglitazone and vitamin E, I think most of us are not using them. We should make it clear that they're not approved by the US Food and Drug Administration (FDA) for this indication but certainly can be used in that setting. Pioglitazone has some issues with edema, fluid retention, and other potential cardiovascular issues. That may be one of the reasons its use hasn't taken off.

Weight Loss: A Modest Intervention With Maximum Impact

Baum: I'd like to return to the weight loss issue. It has been shown in the literature that weight loss of up to, for example, 10% can cause anything from regression of fat in the liver, regression of fibrosis, to even resolution of NASH. However, to experience those benefits, the weight loss has to be sustained. Are you finding ways to help patients achieve that?

Shubrook: Well, we can always do better. I think often the most optimistic goal for NAFLD is 5% weight loss. I really try to work with my patients to let them know that we're likely not going to lose 80 pounds, so we should instead focus on meaningful but small weight loss changes at the beginning.

We use the Diabetes Prevention Program or perhaps low-calorie interventions like those studied in the DiRECT Trial. The goal is really to achieve that initial weight loss. We inform them of the kinds of benefits they get from 5%-7% weight loss. We focus on that as our primary outcome with frequent, supervised touchpoints. Too often, at least in physician care, we don't get enough touchpoints for the patients, so these programs provide them with that in order to slowly but steadily achieve their goals.

Baum: What kind of sustained weight loss levels are you seeing?

Shubrook: We've had a net 5% weight loss among participants in these programs, although of course it varies. Again, that's only after a year, and this needs to be maintained for the rest of patients' lives. But this is better than what we've had in the past. Historically, the average person gains a pound per year every year. This is a step forward, showing that it can be improved.

Baum: That's wonderful.

It Takes Teamwork to Treat Fatty Liver Disease

Shubrook: What I've really learned is that, particularly with diabetes and its related complications, we're all in this soup together. We've got endocrinologists, hepatologists, cardiologists, nephrologists, and primary care docs all working together. How do you think we ensure that such a team-based approach works in the future?

Baum: It would be wonderful to have a team-based approach. I'm sure that with guidelines that you've been spearheading, we'll have some wonderful suggestions about that.

However, I currently don't see this as being very pragmatic in typical practice, outside of an academic center where we're all sort of siloed. I see that as a very challenging issue. I'm hopeful that there are going to be ways to do it, and I wish I had the answer, but I don't right now.

Shubrook: How can primary care physicians best work with a cardiologist with these patients?

Baum: The first step would be to identify that high-risk patient with possible NASH. Once that's done, you can potentially refer them to a center for a fiber scan, sort of a fancy ultrasound that can determine pretty well the degree of fibrosis and fat in a liver. That helps give you a better sense of who that patient is and their level of risk.

Then I would recommend sending them to cardiology earlier rather than later. The reason for that is it would enhance the cardiologist's focus on these patients and thereby improve therapeutics that can reduce cardiovascular risk.

We started out talking about the fact that there is certainly an increased risk for cardiovascular events and cardiovascular death in this patient population. Maybe it's independent. There are a few studies looking at this, such as evidence showing an increase in intima-media thickness in patients based on their degree of fat in the liver. Another study, by Kim and colleagues in South Korea, showed that people who have a zero coronary artery calcium score 4 years later have a twofold increased risk of developing coronary artery calcium if they have fatty liver. We understand that coronary calcium is highly predictive of cardiovascular events. The MESA study showed that if one has a calcium score > 300, there's a 10-fold increase in the risk for major cardiac events. This is really important to monitor now that we've shown that calcium is increased in patients with fatty liver disease and fibrosis.

Other studies have shown an increased risk for associated death, including Pisto and colleagues', who reported increased cardiovascular mortality in patients based on their degree of fibrosis. Now, that doesn't prove independence and causation, but we certainly are getting a sense of an independent risk associated with NASH and cardiovascular disease.

So, I think focusing the cardiologist's attention on reducing cardiovascular risk will have a tremendous impact. It will also help that team approach by allowing you to lower the individual patient's risk.

Fat's Dangerous and Cascading Effects

Shubrook: It's always that tip-of-the-iceberg story when we see someone who has truncal obesity, maybe steatosis on their ultrasound, maybe elevated transaminase levels, although that's not always present. It's like with vascular disease; when you have blockage somewhere, you have blockage everywhere. That's how I think of things.

It's important for us to start approaching obesity as not just a body habitus problem. This is a problem that can cause inflammation, liver problems, cardiovascular problems. We really need to heed that warning and take a very serious approach early on, because what I'm hearing from you is that by doing so we could be preventing events.

Baum: Absolutely. And that brings us to the issue of lipotoxicity, which is generalized fat being toxic. We don't typically think of fat that way, but the term lipotoxicity has made its way into the literature for a reason. What are your thoughts about that?

Shubrook: We see this a lot in diabetes, of course. People can have kind of abnormal responses to meals — for example, postprandial hypertriglyceridemia — which really can be quite toxic to the body. It can cause things like fatty liver, it can impair glucose tolerance, it can stun the pancreas.

It's important for us to know that fat belongs in certain places in our body and is an important storage vehicle when it's normal, but excessive fat in the wrong place is an inflammatory marker. It's something that causes all kinds of bad actions. Although we don't have perfect markers of measuring it, we certainly see its effects regularly, in both the cardiovascular and endocrine worlds. We certainly see hypertriglyceridemia when people decompensate quickly.

It's a really important factor and it's all connected. As much as we practice in different silos, the body is a single unit that all works together.

Baum: I think that's a great idea for you, as the primary care physician, to take a lead on this and proactively refer out to a cardiologist, hepatologist, nutritionist, etc. Getting that team-based approach would be wonderful. If you could manage that in the private-practice setting, that would be phenomenal and a big win.

Shubrook: Where I've had the most successful team-based care is when we have bidirectional communication. I would challenge all the primary care providers out there to say if you're going to do a referral, send a note explaining what it is that you want from that. Sometimes they'll have a unique perspective and see things that we don't see, but having a clear direction starts that process.

Baum: I laugh because when I first started in practice as an interventional cardiologist and electrophysiologist, all I did was procedures. I remember going into private practice and on maybe my first day, getting a consult that simply read, "Cath." I was like, "Wait a second — aren't you going to call me to discuss this? Why do you want the patient to have a cath?"

Somehow, when we step out of training, we forget that communication is really, really important for appropriately managing our patients.

Shubrook: If I'm going to steer a person's healthcare, then I need to take the lead on that and communicate. Then I'll expect a communication back. I work in a specialty silo as well with diabetes, and often we'll just do whatever we have to do. But it doesn't create that team environment.

Looking Ahead

Shubrook: There are some exciting treatments in development related to NAFLD and NASH. We're learning that some of the new diabetes medications might be beneficial, such as glucagon-like peptide 1 receptor agonists, and there are even some early signals with sodium-glucose cotransporter-2 (SGLT2) inhibitors. Of course, we know that they also have cardiovascular benefit. Are there other things that you're seeing that may be beneficial for fatty liver disease?

Baum: There are approximately 50 drugs in development right now for NASH and NASH with fibrosis. They are categorized really in those anti-inflammatory, antifibrotic, and metabolic-improving categories. Thyroid hormone receptor beta agonists are really far along in development. Fibroblast growth factor agonists are being used. Endogenous metabolic modulators, which are high-dose specific amino acids that have been formulated to render a particular effect, are in development. The list goes on and on. I've participated in a large number of clinical trials for fatty liver. I'm always impressed by the novel mechanisms of actions of these medications.

Unfortunately, at this point, there's no winner. We don't have a drug that's received FDA approval. I think there are a couple that are getting close, though. And once the first one gets across the line, I think the game really changes, because whenever we have a new drug in our armamentarium to help battle a disorder, then we really start to focus on it.

Shubrook: In summary, today focused on how prevalent NAFLD and NASH are in all of our practices. We talked about how this affects all of our practices in different ways, including by promoting adverse cardiovascular outcomes.

We must highlight that therapeutic weight loss, if it can be sustained, helps all of these things that we're talking about. To help patients achieve that weight loss, we should have as many touchpoints as possible when we supervise and assist them.

We should also be considering NAFLD as an inflammatory disorder, as something that we need to take seriously and approach in different ways to identify. A team-based approach really could optimize the patient's care in that regard.

Currently we don't have great guidance for dealing with this, with all kinds of conflicting and inconsistent recommendations. The American Gastroenterologic Association with Knighten Health convened panels of multiple specialties last year, including the American Diabetes Association and the American College of Osteopathic Family Physicians. I recommend that readers stay tuned about that. There's a paper in press that hopefully you'll see later this year, which will really try to bring all of that together in a clean pathway uniting primary care and specialty care so that we can do the best job we can for our patients.

Thank you so much. I really enjoyed talking, and I look forward to working with you in the future.

Baum: Thanks, Jay. It was a great time, and I look forward to reading your pathway.

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