Fatty liver still unseen in the metabolic ‘constellation of risk’
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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.
NAFLD’S progression to nonalcoholic steatohepatitis (NASH) quickly became the leading indication for liver transplant. Yet, most patients with NAFLD die of CVD, not liver disease.
“The problem is the spectrum in cardiovascular disease occurs irrespective of the extent of liver disease. Cardiovascular disease can occur in patients with liver disease ranging from F0 to F4 while liver morbidity occurs only with advanced fibrosis. Cardiovascular disease is a big issue, and it is the number one cause of death in NASH patients,” Eric J. Lawitz, MD, medical director of the Texas Liver Institute and a clinical professor of medicine at University of Texas Health Science Center in San Antonio, told Healio Gastroenterology. “We have to understand that the metabolic syndrome is a cluster of conditions that occur together and subsequently affect numerous organs. The liver manifestation is NASH, which has been ignored because we have not had effective interventions. It’s been at the bottom of the list in complications of the metabolic syndrome.”
Collaboration is needed among hepatologists, gastroenterologists, cardiologists, endocrinologists, primary care physicians, nutritionists and exercise physiologists, experts told Healio Gastroenterology.
Hepatologists need to raise the awareness levels among cardiologists, endocrinologists and primary care physicians so they might link obesity and insulin resistance with both cardiometabolic conditions and NAFLD and NASH so that diagnoses are not missed or patients at higher risk for complications from advanced liver disease.
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 Healio Gastroenterology.
Parallels Between Liver, Heart Conditions
Manifestations of the liver and heart interactions affect many of the conditions that physicians commonly see in their patients. Although the association between NAFLD, NASH and CVD is well established, the underlying mechanisms at play are still under investigation.
“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 Healio Gastroenterology. “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,” Mantzoros said.
Patients also often have insulin resistance, with about 70% of patients with type 2 diabetes also having NAFLD. Obesity is another key common denominator.
“Many of our patients are insulin resistant, and the risk for advanced fibrosis is significantly higher in those with type 2 diabetes” Rohit Loomba, MD, MHSc, professor of medicine at University of California San Diego School of Medicine, and founding director of the UC San Diego NAFLD Research Center, told Healio Gastroenterology. “What type of diet might be beneficial for them? Typically, we recommend a Mediterranean diet, or a diet that is low in carbohydrate, because it’s really sugar, sugar-containing beverages and fructose-enriched diet, especially high-fructose corn syrup-containing beverages such as sodas, that’s really harmful.
“Furthermore, alcohol use and smoking may also increase the risk for fibrosis progression in patients with NAFLD.”
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.
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.
Loomba explained that as a hepatologist consulting with a patient for the first time, he does a thorough history.
“This is, really important because one of the things that I do with my patients is that when they come to see me is I ask them about their diet, lifestyle and discuss cardiovascular risk factors,” he said.
Alcohol consumption, which can also complicate liver disease, smoking, exercise and previous cardiac history should be considered when examining a patient for fatty liver disease, he said.
“We all want to have a holistic approach in treating our patients. We want them to feel better, live better in a cleaner environment, and lead a more productive life,” Loomba said. “Not only is improving liver diseases risk important for me, but also cardiovascular risk is critical. And addressing that from the get-go in the first visit when the patient comes to you is important.
“Doing simple things like asking them to stop smoking. Check in if they are taking statin or not, if they have any side effects related to it, or if they’re concerned. ... Just working together and communicating and educating patients and having an open line of communication is key for successful treatment response.”
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 Healio Gastroenterology. “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.
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 [physicians] should be more involved in recognizing the risks of fatty liver disease among their patients.”
Literature reviews show 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. 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.
“I think of NASH as the liver manifestation of the metabolic syndrome. We all need to work together to enhance outcomes in NASH patients. A comprehensive care team is the most beneficial to patients. They can work with the hepatologist on NASH, the cardiologist on cardiovascular disease, the endocrinologist on their diabetes and hypercholesterolemia, a nutritionist/dietician to help them with their diet and even an exercise physiologist to enhance exercise activities,” Lawitz said. “The best approach rather than one specialist or physician trying to be the master of all is having a multidisciplinary approach to these patients. ... The opportunity for the best outcome is by involving specialists who can supply specialty care to the many features and complications of the metabolic syndrome. From the hepatology standpoint, I am hopeful some of these agents in the pipeline can come to fruition and allow us to enhance liver outcomes in those with advanced disease.”
Awareness Among Non-hepatologists
When a patient arrives at a gastroenterology or hepatology clinic after referral from their primary care physician or specialist, Lawitz said it is often the first time the patient is hearing about their risk for liver disease.
“We do need more liver awareness and awareness of NASH by the primary care physicians, particularly being able to identify those with advanced fibrosis,” he said. “It’s important for physicians to identify the patients at most risk of progressive liver disease. The worst thing in the world is to have a patient with the metabolic syndrome for years or decades present with a large hepatocellular cancer due to a lack of identifying cirrhosis and thus never having the opportunity to enter into a hepatocellular cancer screening regimen.”
Lawitz said the use of calculators like the NAFLD fibrosis score and the FIB4 offer an easy way to bring a patient’s risk of advanced liver fibrosis the forefront.
“There’s no magic behind these calculators. ... They force you to plug those important variables in determining the patient’s risk for advanced fibrosis. If the calculators suggest advanced fibrosis, then a referral to a hepatologist or gastroenterologist should be considered so the patient can be monitored for complications of cirrhosis,” he said. “All physicians need to be more aware of liver disease. Everyone knows to treat the diabetes, hypertension and hypercholesterolemia, but there is a lack of awareness of liver disease and risk of complication.”
“We hope there are therapies in the years to come [for NAFLD], but if we identify those patients at the highest risk and be ready to put these patients on therapy if that opportunity arrives in the future,” Lawitz said. “Unfortunately, it’s a travesty when people develop complications of cirrhosis and never even been told they had liver disease.”
Lifestyle Changes, Other Preventive Measures
Prevention of NAFLD, NASH and the associated CV risks can be addressed by lifestyle modifications.
“We’d recommend that the patient start a lifestyle intervention program including exercise,” Loomba said. “A majority of patients are able to start physical activity, and I start with sort of increasing physical activity to say 10,000 steps per day,” gradually moving them into the recommended 30 to 45 minutes five times per week.
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.
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. In agreement, the American Association for the Study of Liver Disease recommends the use of statins in individuals if they do not have compensated cirrhosis.
“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 [patients with NAFLD].”
Loomba and Lawitz agreed.
“Most patients with NAFLD suffer from dyslipidemia, and statins are indicated in that setting, and in fact, we highly recommend that the patient with NAFLD be placed on a statin,” Loomba said.
While it’s understandable that a cardiologist or primary care physician may express concern about elevated liver enzymes when starting a statin, Lawitz said, that the risk-benefit ratio is always tilted to the side of treatment.
“The risk for drug-induced liver disease on statins is small while the benefit is large from a cardiovascular standpoint. We encourage the use of statins appropriately,” Lawitz said. “We don’t have any medications on the market for NASH, but we have many choices to manage features of the metabolic syndrome thus we need to use available medications to maximize treatment of diabetes, hypertension and dyslipidemia.”
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.”
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.
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 [physician] 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.”
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.”
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.
Lawitz discussed a recent The New England Journal of Medicine paper that showed a GLP-1 agonists had positive effects on NASH and importantly was associated with weight loss. There are several other therapies in phase 3 clinical trials for which we are waiting on results.
“As new therapies come along, it will be important to make sure that the therapies are safe from a cardiovascular viewpoint, as well as a liver standpoint in patients for NAFLD,” Loomba said.
- References:
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- Sperling LS, et al. J Am Coll Cardiol. 2015;doi:10.1016/j.jacc.2015.06.1328.
- Stahl EP, et al. J Am Coll Cardiol. 2019;doi:10.1016/j.jacc.2018.11.050.
- Taub PR. Session III: Nonalcoholic fatty liver disease and risk of cardiovascular disease: What clinicians need to know. Presented at: National Lipid Association Scientific Sessions; Dec. 10-12, 2020 (virtual meeting).
- Wilkinson MJ. Session III: Nonalcoholic fatty liver disease and risk of cardiovascular disease: What clinicians need to know. Presented at: National Lipid Association Scientific Sessions; Dec. 10-12, 2020 (virtual meeting).
- For more information:
- Kenneth Cusi, MD, FACP, FACE, can be reached at The University of Florida,1600 SW Archer Rd., Room H-2, P.O. Box 100226, Gainesville, FL 32610; email: kenneth.cusi@medicine.ufl.edu.
- Eric Lawitz, MD, can be reached at the Texas Liver Institute, 607 Camden St., San Antonio, TX 78215; email: lawitz@txliver.com.
- Rohit Loomba, MD, MHSc, can be reached at the University of California, San Diego, 4510 Executive Dr., San Diego, CA 92121; email: roloomba@health.ucsd.edu; Twitter: @DrLoomba.
- Christos S. Mantzoros, MD, DSc, PhD, can be reached at Harvard Medical School, 25 Shattuck St., Boston, MA 02115; email: cmantzor@bidmc.harvard.edu.
- Laurence S. Sperling, MD, FACC, FACP, FAHA, FASPC, can be reached at Emory University, 201 Dowman Dr., Atlanta, GA 30322; email: lsperli@emory.edu.
- Michael J. Wilkinson, MD, FACC, can be reached at UC San Diego Health System, 200 W. Arbor Dr., San Diego, CA 92103; email: jbvazquez@health.ucsd.edu; Twitter: @MWilkinsonMD.
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