Issue: April 2021
Source: Stahl EP, et al. J Am Coll Cardiol. 2019;doi:10.1016/j.jacc.2018.11.050.
Disclosures: Cusi and Sperling report no relevant financial disclosures. Mantzoros reports he has financial ties with many pharmaceutical companies. Taub reports she consults for Amgen, Boehringer Ingelheim, Esperion, Novo Nordisk and Sanofi. Wilkinson reports he received a research grant from Amgen.
April 20, 2021
10 min read
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Intersection between heart and liver ‘a rapidly evolving field’

Issue: April 2021
Source: Stahl EP, et al. J Am Coll Cardiol. 2019;doi:10.1016/j.jacc.2018.11.050.
Disclosures: Cusi and Sperling report no relevant financial disclosures. Mantzoros reports he has financial ties with many pharmaceutical companies. Taub reports she consults for Amgen, Boehringer Ingelheim, Esperion, Novo Nordisk and Sanofi. Wilkinson reports he received a research grant from Amgen.
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About 25% of U.S. adults have nonalcoholic fatty liver disease, which is the most common chronic liver condition in the U.S., according to the American Liver Foundation.

Nonalcoholic fatty liver disease, known as NAFLD, can progress to nonalcoholic steatohepatitis (NASH), which is a leading indication for liver transplant. Surprisingly, most patients with NAFLD die of CVD, not liver disease.

Pam R. Taub, MD, FACC, from the University of California, San Diego, discusses the links between liver diseases and CVD.

Source: UC San Diego Health Sciences. Reprinted with permission.

“NAFLD and NASH are multisystem conditions that affect many organs. It may appear a bit counterintuitive for a condition that affects the liver to be linked with mortality from cardiovascular disease, but the risk factors for both cardiovascular disease and NAFLD are the same,” Pam R. Taub, MD, FACC, founder and director of Step Family Cardiac Rehabilitation and Wellness Center, and associate professor of medicine at UC San Diego Health System, said during a session at the 2020 virtual National Lipid Association Scientific Sessions, which focused on the intersection between NAFLD, NASH and the associated risk for cardiometabolic disease.

Collaboration is needed among cardiologists, hepatologists, endocrinologists, primary care physicians, nutritionists and exercise physiologists, experts told Cardiology Today.

Focus on the link between obesity and insulin resistance and both cardiometabolic conditions and NAFLD and NASH so that cases and diagnoses are not missed. This is “a rapidly evolving field” that requires vigilance, Christos S. Mantzoros, MD, DSc, PhD, professor of medicine at Harvard Medical School and chief of endocrinology at VA Boston Healthcare System, told Cardiology Today.

Experts discussed how NAFLD and NASH contribute to cardiometabolic risk, the CV implications of the conditions, how these patients can best be managed, to what extent cardiologists should be involved in that management and the medications or other therapies that have been shown to help this growing patient population.

Parallels between liver, heart conditions

Manifestations of the liver and heart interactions affect many of the conditions that cardiologists commonly see in their patients. Although the association between NAFLD, NASH and CVD is well established, the underlying mechanisms at play have not been as well studied. There have, however, been reviews published in the Journal of the American College of Cardiology (March 2019) and in Circulation Research (February 2020) summarizing the rationale for NAFLD as a risk factor for CVD, proposing mechanistic reasons behind the relationship and offering treatment strategies.

“Among the constellation of factors that affect cardiometabolic health, included in that is fatty liver disease,” Laurence S. Sperling, MD, FACC, FACP, FAHA, FASPC, the Katz Professor in Preventive Cardiology at Emory University and founder of Emory Center for Heart Disease Prevention, told Cardiology Today. “Fatty liver disease should not be thought of as an independent entity, but an entity that is part of the greater cardiometabolic constellation of risk. The intersection between the heart and liver is an important intersection to be aware of.”

According to Mantzoros, “The intersection of NAFLD, NASH and cardiometabolic disease stems from the abnormal signaling that occurs when fat is deposited into other places within the body.

“When the body needs to store calories that exceed the storage space of adipose tissue — genetically, epigenetically and environmentally determined — the excess fat gets deposited into other organs that should not contain a lot of fat. Excess fat in muscle then causes insulin resistance, in the liver causes NAFLD and NASH, and in the vasculature causes atherosclerotic cardiovascular disease. All of these are linked with each other through excess fat deposition, insulin resistance, inflammation and fibrosis,” Mantzoros said.

Taub said NAFLD can be considered a CVD risk factor in the same way that type 2 diabetes is considered part of the CVD spectrum. These patients have insulin resistance, with about 70% of patients with type 2 diabetes also having NAFLD.

Christos S. Mantzoros

Obesity is another key common denominator.

Results of a study published in 2018 in Surgery for Obesity and Related Diseases showed 95% of patients with obesity undergoing bariatric surgery had NAFLD. Moreover, NASH was diagnosed in 59.4% of patients with diabetes and in 49.2% of those considered prediabetic.

“When we see an obese person with insulin resistance or diabetes, we need to suspect not only cardiometabolic disorders but also the potential for kidney disease and liver problems,” Mantzoros said. “The most common cardiovascular issues among these patients are cardiometabolic abnormalities, atherosclerotic vascular disease and sometimes even heart failure.”

Sperling agreed. “The metabolic syndrome has many different manifestations and cardiologists are aware of the frequent manifestations that lead patients to acute coronary syndromes, including diabetes, metabolic dyslipidemia and hypertension.”

Beyond the risk for MI and vascular problems, the consequences of the interaction between NAFLD, NASH and CVD appear to affect the risk for structural and valvular changes. There also appears to be increased risk for atrial fibrillation and autonomic dysfunction in individuals with fatty liver disease, Sperling said.

Fatty liver disease is more prevalent in men than in women, but “no one knows exactly why,” Kenneth Cusi, MD, FACP, FACE, chief of the division of endocrinology, diabetes and metabolism at the University of Florida, told Cardiology Today. “People with NAFLD tend to have lower testosterone, but it’s not linked to the severity of liver histology.”

Social determinants of health are also presumed to play a role.

Kenneth Cusi

Sperling said there are stages of cardiometabolic risk, “where ‘stage A’ is when someone is at risk for cardiometabolic disease, which may include genetic risk, an effect of social determinants of health or it may be a combination of the two. This risk begins during childhood and propagates during adolescence, and points to the fact that cardiologists should be more involved in recognizing the risks of fatty liver disease among their patients. As opposed to cardiologists focusing on the consequences of these problems, being champions and active team members in the prevention of them in the first place can impact overall cardiovascular health.”

The JACC review identified the following as factors in the relationship between NAFLD and CVD: altered lipid metabolism, endothelial dysfunction, oxidative stress, plaque formation/instability, systemic inflammation and systemic insulin resistance. The Circulation Research review noted fatty liver disturbs lipid metabolism and hepatokines; drives systemic inflammation; activates, along with metabolic syndrome, the neuroendocrine system to increase vascular tone; activates thrombosis and embolism; accelerates oxidative stress; and contributes to intestinal dysbiosis.

Lifestyle changes, other preventive measures

Prevention of NAFLD, NASH and the associated CV risks can be addressed by lifestyle modifications.

“From a population health standpoint, it is imperative that the obesity and cardiometabolic epidemics are addressed at the level of diet and exercise, as modest weight loss, lifestyle and behavioral changes can help prevent and regress fatty liver disease,” Taub said. “Aggressive treatment of the underlying risk factors is important, and it would be beneficial to address some of these factors very early on. As soon as there is any evidence of fatty liver disease would be a good time to get the patient to engage in weight loss and other strategies that improve insulin resistance.”

In addition to lifestyle changes, use of vitamin E as well as targeted medications among patients with diabetes can prevent progression of NAFLD and NASH. In one trial, vitamin E was superior to placebo at improving NASH without increasing adverse events.

“These include GLP-1 receptor agonists, SGLT2 inhibitors and pioglitazone,” Taub said. “For patients with dyslipidemia, it is imperative to treat the condition aggressively by starting the patient on a statin. In many clinical scenarios, clinicians are often scared to start statins in these patients because they have mildly elevated liver function tests. However, all data show that statins are safe in these patients and should be started. Also, if the patient has hypertension, that condition should be treated aggressively.”

Sperling, who was on the writing committee for the 2018 ACC/American Heart Association Guideline on the Management of Blood Cholesterol, said there are data that suggest statins have a cardioprotective effect on individuals with fatty liver disease.

“One of the recommendations in the guideline is that statins appear safe in those with stable liver disease,” Sperling said. “What leads cardiologists and other clinicians in the wrong direction frequently is that they see a patient with mildly elevated liver enzymes and then shy away from preventive therapies such as statins. However, it is safe to use statins in this patient population.”

Laurence S. Sperling

Strategies for symptom improvement

Weight loss and lifestyle changes are the main ways to improve symptoms of NAFLD; however, medications can be used to address conditions associated with NAFLD such as dyslipidemia, insulin resistance, hepatic apoptosis, inflammation and fibrosis, according to Michael J. Wilkinson, MD, FACC, assistant professor of medicine at the University of California, San Diego, and the Cardiovascular Institute at UC San Diego Health.

Wilkinson addressed the importance of treating the common conditions in patients with NAFLD during his presentation at the National Lipid Association Scientific Sessions.

“NAFLD is common in patients with diabetes, obesity and/or the metabolic syndrome, and it contributes to elevated risk for cardiovascular disease, which means treating those conditions is just as important as treating the NAFLD itself,” Wilkinson said. “Statins should be first-line therapy in patients with NAFLD, even in most of those for whom it has progressed to NASH.”

Data from a post hoc analysis of the GREACE study, published in 2010 in The Lancet, showed statins were safe and appeared to improve liver function tests and reduce CV morbidity among a cohort of patients with mild to moderately abnormal liver tests potentially associated with NAFLD.

“There was not an increased risk for liver-related adverse events in patients taking statins for primary prevention,” Wilkinson said. “In fact, the data show that not only did statins reduce the risk for cardiovascular events, but they also reduced transaminase levels. There should be no hesitation for providers to treat patients with NAFLD and NASH with statin therapy if they meet guideline-based recommendations for statin therapy for primary prevention of cardiovascular disease.”

A review published in 2018 in Current Pharmaceutical Design found that two other trials, as well as numerous case reports, confirmed the results of GREACE.

However, Cusi said in an interview, GREACE “was a poor-quality study” because it was uncontrolled. “Observational studies suggest beneficial effects that require controlled trials to confirm. But in placebo-controlled biopsy studies, statins have not been associated with a beneficial effect on liver histology in NASH,” he said.

He noted, however, that “Overall, statins are not harmful. The statin should not be discontinued due to mild to moderate elevation in liver enzymes; they are typically not associated with harm, but they have a number of pleotropic beneficial effects. They are not harmful and may be helpful, but right now, we cannot advocate their use to treat NASH.”

Other treatment options include GLP-1 receptor agonists and SGLT2 inhibitors, as well as bariatric surgery to counteract both the progression and development of CVD from NAFLD and NASH.

Michael J. Wilkinson

“Still, it is important for the cardiologist to think about the benefit of combination therapy for these patients,” Sperling said. “When we think about combination therapy, we often think about the combination of various medications, but first and foremost, combination therapy should involve a lifestyle and behavioral intervention.”

A challenge in managing these patients, Sperling added, is that the disease process for NAFLD and NASH is similar to atherosclerosis, for which no single medication completely abolishes it.

“This is why we need a multipronged approach that will address lipotoxicity inflammation fibrogenesis, because when the liver is inflamed, it goes through various disease stages just like the arteries and heart do,” Sperling said. “Cardiologists will understand that the process of developing a fatty liver is very similar to atherosclerosis and eventually leads to an end-stage process in cirrhosis. Until these patients get to late-stage NASH or begin to develop late-stage cirrhosis, the risk for adverse events are greater in the realm of heart disease, not liver disease.”

Research underway

As the burden of NAFLD and NASH has significantly increased in the U.S. and around the world, the pharmaceutical industry is investing much effort into developing pharmacotherapies for this patient population.

“We are calling this the ‘dash for the NASH cure’ where industry is investing a lot of time and money to try to find medications that could affect the pathophysiology of fatty liver disease,” Sperling said. “There is an explosion of phase 2 and phase 3 clinical trials, with around 160 drugs currently in the developmental phase.”

Taub said more research is still needed to identify effective targeted lifestyle interventions.

“For instance, we tell our patients the same lifestyle strategies of lose weight, eat better and exercise more,” Taub said. “But it would be great if we could be more specific. Maybe patients who have NAFLD and NASH need a specific type of exercise regimen that improves skeletal muscle and insulin resistance, which would be a good area for research. We also need to come up with good pharmacologic treatments that prevent and/or decrease inflammation in the liver as well as treatments that could reduce the risk for fibrosis.”

In addition, research is needed to identify biomarkers for early diagnosis of NAFLD and NASH, according to Taub.

“It would be great to have better biomarkers to diagnose these conditions early instead of relying on imaging and liver function tests that are often unreliable, as we know that numbers can be normal during the early stages of disease,” Taub said.

Mantzoros said FDA-approved therapies are still needed to address certain aspects of NAFLD and NASH.

“Unfortunately, we do not have any specific treatments yet for NAFLD and NASH except for lifestyle modifications including exercise and a healthy diet,” Mantzoros said. “Many medications are now in phase 2 and phase 3 development. Further clinical research with medications that improve cardiometabolic conditions are expected to improve outcomes in NAFLD and NASH. However, whether medications in trials for NAFLD and NASH also improve cardiometabolic conditions remains to be seen, but we may find out in the next couple of years.” – by Jennifer Southall , with additional reporting by Regina Schaffer