Issue: October 2021
Disclosures: Cusi, DiStefano and Sperling report no relevant financial disclosures. Klein reports receiving advisory board fees from Altimmune and Merck and research funding from Johnson & Johnson. Wilkinson reports receiving a research grant from Amgen.
October 18, 2021
10 min read
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Intersection between heart and liver a rapidly evolving field

Issue: October 2021
Disclosures: Cusi, DiStefano and Sperling report no relevant financial disclosures. Klein reports receiving advisory board fees from Altimmune and Merck and research funding from Johnson & Johnson. Wilkinson reports receiving 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. However, most patients with NAFLD die of cardiovascular disease, not liver disease.

Fatty liver is being recognized as a strong determinant of cardiometabolic disorders, CVD and even certain kinds of cancers, according to Johanna K. DiStefano, PhD.

Photo courtesy of Johanna K. DiStefano. Printed with permission.

“It should not be a surprise to us that people with fatty liver die from cardiovascular disease,” Johanna K. DiStefano, PhD, professor and head of the diabetes and fibrotic disease unit at the Translational Genomics Research Institute in Phoenix, told Endocrine Today. “The [diseases] sprout from the same soil. Many people who have CVD have insulin resistance, have overweight or obesity, and have dyslipidemia. Fatty liver is emerging in the clinical arena as a strong determinant of not only CVD, but diabetes and even certain kinds of cancers.”

In July, eight professional societies published a “call to action” on the dangers associated with NAFLD and NASH, calling on clinicians to work together across specialties and align treatment strategies. The joint report noted collaboration is needed among endocrinologists, cardiologists, hepatologists, primary care physicians, nutritionists and exercise physiologists to tackle what experts call a growing NASH epidemic.

Endocrinologists must consider NAFLD as part of the “constellation of metabolic abnormalities” associated with obesity that causes CVD, Samuel Klein, MD, the William H. Danforth Professor of Medicine and Nutritional Science and director of the Center for Human Nutrition at Washington University School of Medicine, St. Louis, told Endocrine Today.

“Obesity causes insulin resistance and beta-cell dysfunction, type 2 diabetes, NAFLD and dyslipidemia, and even high blood pressure,” Klein said. “Those are all risk factors for CVD. NAFLD is not an independent disease — these all track together. It is a biomarker for a person at high risk for cardiometabolic complications.”

Samuel Klein

Parallels between liver, heart conditions

Manifestations of the liver and heart interactions affect many of the conditions that endocrinologists and 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. Reviews published in the Journal of the American College of Cardiology (March 2019) and in Circulation Research (February 2020) summarize the rationale for NAFLD as a risk factor for CVD, propose mechanistic reasons behind the relationship and offer treatment strategies.

Data from observational studies also show pathways that might connect fatty liver and CVD, DiStefano said.

“These include inflammation, lipogenesis and, surprisingly, gut dysbiosis,” DiStefano said. “There are also links to suggest that fatty liver can directly affect CVD risk in people, even among people with normal weight.”

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

Laurence S. Sperling

Obesity is another key common denominator, she said.

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 to have prediabetes.

“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,” 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 Endocrine Today.

Beyond the risk for myocardial infarction and vascular problems, the consequences of the interaction between NAFLD, NASH and CVD appear to affect the risks 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 Endocrine 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 presumed to play a role and influence stages of cardiometabolic risk, Sperling said.

“’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,” Sperling said. “This risk begins during childhood and propagates during adolescence, and points to the fact that endocrinologists and cardiologists should be more involved in recognizing the risks of fatty liver disease among their patients. As opposed to 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.”

Kenneth Cusi

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 with lifestyle modifications; however, medications can be used to address conditions associated with NAFLD, such as dyslipidemia, insulin resistance, hepatic apoptosis, inflammation and fibrosis. There are currently no FDA-approved therapies indicated for NAFLD.

“The cornerstone of therapy is weight loss,” Klein said. “That means significant weight loss and keeping it off, long term; however, even small amounts of weight loss can reduce liver fat dramatically. The liver is very sensitive to changes in energy balance.”

Lifestyle therapy, which Klein said should ideally be referred out to an expert center, will not work for all people with NAFLD, who often struggle to maintain weight loss.

“If lifestyle therapy is not effective, medications are the next step,” Klein said. “Now we have medications recently approved that have potent effects on body weight. Newer agents are in development that might really add to what we see now with GLP-1 receptor agonists that can treat obesity and ultimately treat NAFLD.”

Use of vitamin E as well as targeted medications for 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.

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.

“Still, it is important for the endocrinologist or 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.”

Use of statins debated

Sperling, who was on the writing committee for the 2018 American College of Cardiology/American Heart Association Guideline on the Management of Blood Cholesterol, said data 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.”

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, said statins should be first-line therapy for patients with NAFLD, even for those who progressed to NASH.

Michael J. Wilkinson

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, but noted the evidence was strongest for atorvastatin and rosuvastatin.

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,” Cusi 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.”

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

“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 risks 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.”

DiStefano said researchers must better categorize the etiology of fatty liver in the individual, which can vary.

“For example, postmenopausal women with fatty liver need to be managed differently than a man aged 25 years with a BMI of 30 kg/m2,” DiStefano said. “In the obese population, a very good strategy is bariatric surgery. In the diabetes population, some diabetes drugs are effective. Even after progressing to liver transplant, the risk for developing fatty liver again is quite high. The other issue is the emergence of so-called ‘lean’ NAFLD — fatty liver in people with normal weight. These are people without metabolic risk factors. We need to know their CV risk.”

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

“There is this idea that your liver enzymes are going to be off if there is a problem, but that is not always true,” DiStefano said. “Most fatty liver is diagnosed incidentally because there is something else going on.”

In addition to a need for FDA-approved therapies, Klein said, more research is needed to understand why some people progress to NASH while others with fatty liver do not.

“Insulin resistance — and having a high insulin concentration — stimulates de novo lipogenesis in the liver, whereas having increased glucose and fatty acids in the bloodstream leads to increased triglyceride production in the liver,” Klein said. “Those are all aspects of why we see fatty liver disease. But 85% of people with increased fat in the liver do not progress to NASH. That is the question: What is the mechanism behind why some people go from fatty liver, which is really relatively benign, to a more severe form of inflammation and fibrosis that is much more deadly? If we can understand what causes that progression, that would go a long way in treating the disease. Why does NAFL become NAFLD?”

As that research continues, endocrinologists and other clinicians must “put NAFLD on the radar screen,” Klein said.

“Whenever you have someone at risk for CV complications from being obese, for example, you should also be looking for fatty liver because that is another risk factor,” Klein said. “If someone has increased fat in the liver, they are at higher risk for CVD as well. That is when you should go a little further to see if they have a serious increase in abnormalities in the liver, such as fibrosis, which requires further testing. It is about making NAFLD a part of your medical evaluation and looking at the entire elephant, not just individual organ systems. You must include liver disease as part of your metabolic assessment.”