There is a silent disease lurking in virtually every internal medicine clinic in America.
Nonalcoholic fatty liver disease (NAFLD) has no reliable symptoms—only risk factors—and can progress to advanced liver disease. It has quickly become the most common chronic liver disease in the U.S., said hepatologist Scott Matherly, MD, an associate professor of medicine at Virginia Commonwealth University School of Medicine in Richmond.
“The prevalence of fatty liver disease is closely linked with that of obesity. As more people become obese, more people develop fatty liver disease,” he said. “The most recent prevalence estimates put it at about 25% of adults. We only expect this to worsen over time.”
As a hepatologist, Mary Rinella, MD, has received referrals of patients who developed complications related to cirrhosis but who were not previously appreciated to have NAFLD. “Patients with advanced liver disease from NASH [nonalcoholic steatohepatitis], even cirrhosis, are being seen unknowingly by many internists—and they're just not aware of it. … Unless you're really thinking about it and really looking for it, it can be tough to pick up,” she said.
Not only has NAFLD been associated with COVID-19 morbidity and mortality, it is also associated with a significantly increased risk for other adverse outcomes, said Dr. Rinella, a professor of medicine at Northwestern University Feinberg School of Medicine in Chicago and the director of the Northwestern Fatty Liver Program.
“From an internist's perspective, I think [NAFLD] is particularly important because it's likely to be an independent driver of cardiovascular mortality, and it certainly is independently associated with diabetes and hypertension,” she said.
For internists who want to improve outcomes for patients with NAFLD, “There's no time like the present,” Dr. Rinella said. She and other experts explained how identifying NAFLD in the primary care setting and deploying effective interventions early can help prevent the slowly progressive disease from becoming an even bigger problem.
Making the diagnosis
While understanding the pathophysiology of NAFLD has been complicated due to difficulties in obtaining liver tissue through biopsy, research has found that fat in the liver can lead to chronic inflammation that activates fibrosis, explained Kenneth Cusi, MD, FACP, a professor of medicine and chief of the division of endocrinology, diabetes, and metabolism at the University of Florida in Gainesville.
“Insulin resistance and adipose tissue create the conditions for triglyceride accumulation in the liver cells. It also causes resistance in the muscle and creates an environment that predisposes the liver to accumulate fat and trigger inflammation. … The most common observation has been that people with obesity—but in particular, obesity and diabetes—get it much more often,” he said.
Routinely screening patients for NAFLD—even those at high risk—is not currently recommended by the American Association for the Study of Liver Diseases (AASLD). In practice guidance published in January 2018 by Hepatology, authors (including Drs. Rinella and Cusi) maintained that screening is not currently advised because of uncertainties around diagnostic tests and treatment options, along with knowledge gaps related to long-term benefits and cost-effectiveness of screening.
However, clinicians should have “a high index of suspicion for NAFLD and NASH in patients with type 2 diabetes,” the guidance said. Future guidance may consider officially recommending screening for NAFLD in patients with diabetes, Dr. Rinella said. Of note, Dr. Cusi and coauthors called for more aggressive screening in patients with obesity and diabetes after their study in the February Diabetes Care found that about 15% of patients with type 2 diabetes had moderate or severe fibrosis or cirrhosis.
But for now, recognizing the disease boils down to recognizing risk factors, said Dr. Rinella. The strongest risk factors for NAFLD are the presence of obesity (particularly central obesity), diabetes, hypertension, and age over 50 years, she said, and other factors, such as obstructive sleep apnea and metabolic dyslipidemia, also increase a patient's risk.
Since most patients with NAFLD are asymptomatic, they often come to clinical attention because of increased liver function tests or an incidental finding on abdominal imaging, said Howard Libman, MD, FACP, an attending physician in the division of general medicine at Beth Israel Deaconess Medical Center in Boston and lead author of a Beyond the Guidelines article on NAFLD published in August 2019 by Annals of Internal Medicine. “The most serious concern in patients with NAFLD is that some will go on to develop fibrosis, which may ultimately lead to cirrhosis and hepatic failure,” he said.
While most people who have NAFLD do not develop progressive liver disease, about 20% will develop NASH, inflammation of the liver associated with the fat, said Dr. Matherly. “People with NASH can develop fibrosis and ultimately cirrhosis as easily as someone with alcohol-related disease or viral hepatitis,” he said. “The challenge for the physician is to figure out who has plain old fatty liver disease and who has NASH.”
One simple and free way for internists to do that is by calculating a score called the Fibrosis-4 (FIB-4) Index for liver fibrosis, which is based on liver biochemistries, age, and platelet count. “At least with that tool, they can exclude people that they need to worry about with a high degree of confidence,” said Dr. Rinella.
Another helpful practice is monitoring liver enzyme levels in high-risk groups, said Dr. Matherly. For instance, he said a normal alanine aminotransferase (ALT) level would be about 20 IU/L for women and 30 IU/L for men. “Values above that may suggest liver injury and should prompt further workup or referral to hepatology,” Dr. Matherly said.
Typically, and in contrast with alcoholic fatty liver disease, the ALT level in a patient with NASH will be higher than the aspartate aminotransferase (AST) level, said Dr. Cusi, who is also a staff endocrinologist at the Malcom Randall Veterans Affairs (VA) Medical Center in Gainesville. “However, when the AST begins going up, and definitely if it's above 40 [IU/L], it's very likely you have fibrosis,” he said. For patients with diabetes, a lower AST cutoff of 38 IU/L would be better, according to a study by Dr. Cusi's group, published in the February 2020 Diabetes Care.
While the first step in diagnosing NAFLD should be high clinical suspicion, making a definitive diagnosis requires either imaging or biopsy, which remains the gold standard, he said. An ultrasound is the quickest test for the presence or absence of fatty liver disease, but it has its limitations, Dr. Cusi said.
“Ultrasound has a high sensitivity for the detection of hepatic steatosis but does not tell us much about liver fibrosis,” he said. “Therefore, AASLD and other guidelines recommend a pathway that relies more on FIB-4 or imaging, such as vibration-controlled transient elastography, as a second step to identify those at low or high risk for advanced fibrosis (bridging fibrosis or cirrhosis).”
If a patient's FIB-4 score is intermediate or high, then further evaluation would include liver stiffness testing through one of these imaging modalities, Dr. Rinella said. “If everybody did get FIB-4 scores on their patients, we would significantly improve our ability to identify people with a low risk of advanced liver disease and identify those at high risk who may need confirmatory testing or benefit from a liver biopsy,” she said.
Dr. Rinella recommended calculating a FIB-4 score for any patient who has been incidentally noted to have hepatic steatosis or who has elevated liver biochemistries that may be related to hepatic steatosis. The score has also been validated in patients with hepatitis C virus and those with alcoholic fatty liver disease.
Treatment and management
While NAFLD and NASH are dynamic processes that can progress and regress, “Lifestyle modification is a must for all patients, irrespective of where they are in their disease stage,” said hepatologist Manal Abdelmalek, MD, FACP, speaking during the Liver Meeting Digital Experience, held last November by the AASLD.
The first step in treatment is to identify all modifiable risk factors, such as obesity, metabolic syndrome, diabetes, dietary risk factors, quality of sleep, behavioral factors that contribute to obesity, and social habits (both smoking and alcohol consumption) that can contribute to fibrosis progression, she said.
The treatment of obesity, in particular, is the foundation of care, she said. And a little weight lost can make a big difference. “Particularly for those patients who have NASH, a 5% reduction in [body mass index] translates into a 25% relative reduction in liver fat by MRI[-derived proton density fat fraction],” said Dr. Abdelmalek, citing a study published in March 2015 by Clinical Gastroenterology and Hepatology. In addition, weight reduction of 4% to 10% consistently improves measures of liver fat and liver aminotransferase levels, according to a systematic review and meta-analysis of 23 randomized trials of patients with NAFLD, published in January 2012 by the Journal of Hepatology.
“Studies have clearly [shown] that weight loss of 10% [reduces] the inflammation of NASH 90% to 100% of the time,” said Dr. Matherly. “If we can get our patients back to just having NAFLD without inflammation, it is a win.”
How to achieve that amount of weight loss, however, has not been clearly defined, he said. For instance, weight loss surgery is clearly beneficial in those who meet criteria for it, said Dr. Matherly, who encourages his patients to deal with NAFLD and NASH through lifestyle change. “Many people think that the disease is either irreversible or they think they have to lose a huge amount of weight to fix it,” he said. “When I tell them that if they lose 15 to 20 pounds, they can prevent further liver damage, their eyes light up. Most people can do that if they put their minds to it.”
While not a nutrition specialist, Dr. Matherly does take time to counsel patients on dietary factors that are notoriously bad for NAFLD. “I term these things CRAP and ask them to avoid them: Carbonated/sweetened beverages, Refined sugar/high-fructose corn syrup, Artificial and Processed Food. The first two are really the key for this condition,” he said. “I frequently refer my patients to a medical weight loss clinic. If they cannot afford that, I work on it with them each visit and utilize free phone apps.”
Dr. Rinella, who often refers these patients to a nutritionist, said many will require this kind of support in order to make and sustain changes to their lifestyle. “You can't just tell somebody to lose weight and then see them again in a year and be surprised that they didn't lose weight,” she said. “I saw one person yesterday that lost 75 pounds after that conversation, so you do see people who really take it to heart and make changes; however, most will require more structured support for lasting weight loss.”
Although there are potential therapies for NAFLD and NASH in the research pipeline, there are currently no FDA-approved treatments. Therefore, “Treatment of comorbidities contributing to NAFLD is really the only backbone that we currently have,” said Dr. Abdelmalek, a professor of medicine at Duke University in Durham, N.C.
Clinical trials have shown certain diabetes medications to be effective, most notably semaglutide and pioglitazone. “Particularly people with diabetes who are obese, if you have to treat them, choose a drug that will also be beneficial for NASH. That is my approach,” said Dr. Cusi.
In an industry-funded phase 2 trial of semaglutide, the glucagon-like peptide-1 receptor agonist was associated with resolution of NASH. There was no significant improvement in liver fibrosis, but fibrosis progression was slowed down, according to results published last November by the New England Journal of Medicine. However, the formulation used in the study was a daily injection that is not currently available, cautioned Dr. Cusi, a study coauthor.
“The formulation we currently have, FDA-approved to treat diabetes only, is a weekly dose,” he said. “They used a daily formulation because they were aiming to get a higher weekly dose.”
Studies of pioglitazone have consistently shown benefits on liver function, liver fat, and NASH resolution, although the drug can lead to weight gain, according to a review published in November 2019 by Systematic Reviews. While randomized trials conducted by Dr. Cusi's group used a 45-mg dose for maximum benefit, he suggested using 30 mg to mitigate weight gain. “The efficacy is probably the largest among any of the available or upcoming drugs, and it works very well,” he said of the drug.
A key difference between the two medications is their cost. Without insurance, semaglutide costs several hundred dollars, “and insurance companies are not going to approve it if you have NASH; they are only going to approve it if you have diabetes,” said Dr. Cusi. In the VA system, he said pioglitazone costs $2.14 per patient per month and semaglutide costs about 60 times more, “so you could treat 60 people with pioglitazone for the cost of one with semaglutide.”
For adult patients without diabetes, vitamin E (800 IU/d) was superior to placebo for the treatment of NASH in the Pioglitazone, Vitamin E, or Placebo for Nonalcoholic Steatohepatitis (PIVENS) trial, published in May 2010 by the New England Journal of Medicine. “I utilize this in select patients who do not have cirrhosis or diabetes,” said Dr. Matherly.
In addition, internists should not stop statins in the vast majority of patients with NAFLD and NASH, Dr. Cusi said. “If they have increased cardiovascular risk but liver enzymes are elevated, many times primary care doctors stop their statins, which is very bad. … We should encourage primary care doctors to keep them on a statin, at least on the lower dose,” he said.
Statins were safe over three years in patients with biopsy-proven NASH, according to results of a prospective study published in the August 2017 Journal of Clinical Endocrinology & Metabolism. The 2018 AASLD guidance recommends statins in patients with NAFLD or NASH; however, statins should be avoided in patients with decompensated cirrhosis, Dr. Cusi said.
NAFLD vs. MAFLD?
As research continues to explore NAFLD treatments, experts in the field are debating the name of the disease itself. An international consensus panel of experts published a policy paper in the May 2020 Gastroenterology suggesting metabolic dysfunction-associated fatty liver disease (MAFLD) as a term that more accurately reflects pathogenesis and can help in patient stratification for management.
Dr. Matherly said he likes the idea of a name change because the term MAFLD removes alcohol from the equation. “First of all, this condition is exploding in the pediatric population, where alcohol plays a very minimal role,” he said. “The second upside is that it makes it easier to diagnose in people who drink some alcohol.”
Dr. Libman agreed. “The name change to MAFLD is reasonable since it more accurately describes the nature of this condition,” he said. “Most patients with NAFLD/MAFLD will have other features of metabolic syndrome, which include hypertension, diabetes mellitus, dyslipidemia, and obesity.”
However, Dr. Rinella cautioned that clinicians should not start referring to the disease by a different name. The proposed name has not been accepted by any of the major liver societies, including the AASLD, and would pose regulatory issues, such as discrepancies in clinical trial end points, she said.
In addition, NAFLD is a heterogeneous disease, and as more is learned about factors like genetics and disease drivers, clinicians will be able to place people into different subtypes, Dr. Rinella said. “So it would be beneficial to wait until that is a little bit better delineated, rather than just swap out the N for an M and not consider all those other complexities,” she said. “We're planning a consensus conference late this year to discuss this with people from all over the world and reach a consensus on a potential name change.”