Nonalcoholic steatohepatitis (NASH) is a progressive liver disease with no approved treatment. Resmetirom is an oral, liver-directed, thyroid hormone receptor beta–selective agonist in development for the treatment of NASH with liver fibrosis.
Methods
We are conducting an ongoing phase 3 trial involving adults with biopsy-confirmed NASH and a fibrosis stage of F1B, F2, or F3 (stages range from F0 [no fibrosis] to F4 [cirrhosis]). Patients were randomly assigned in a 1:1:1 ratio to receive once-daily resmetirom at a dose of 80 mg or 100 mg or placebo. The two primary end points at week 52 were NASH resolution (including a reduction in the nonalcoholic fatty liver disease [NAFLD] activity score by ≥2 points; scores range from 0 to 8, with higher scores indicating more severe disease) with no worsening of fibrosis, and an improvement (reduction) in fibrosis by at least one stage with no worsening of the NAFLD activity score.
Results
Overall, 966 patients formed the primary analysis population (322 in the 80-mg resmetirom group, 323 in the 100-mg resmetirom group, and 321 in the placebo group). NASH resolution with no worsening of fibrosis was achieved in 25.9% of the patients in the 80-mg resmetirom group and 29.9% of those in the 100-mg resmetirom group, as compared with 9.7% of those in the placebo group (P<0.001 for both comparisons with placebo). Fibrosis improvement by at least one stage with no worsening of the NAFLD activity score was achieved in 24.2% of the patients in the 80-mg resmetirom group and 25.9% of those in the 100-mg resmetirom group, as compared with 14.2% of those in the placebo group (P<0.001 for both comparisons with placebo). The change in low-density lipoprotein cholesterol levels from baseline to week 24 was −13.6% in the 80-mg resmetirom group and −16.3% in the 100-mg resmetirom group, as compared with 0.1% in the placebo group (P<0.001 for both comparisons with placebo). Diarrhea and nausea were more frequent with resmetirom than with placebo. The incidence of serious adverse events was similar across trial groups: 10.9% in the 80-mg resmetirom group, 12.7% in the 100-mg resmetirom group, and 11.5% in the placebo group.
Conclusions
Both the 80-mg dose and the 100-mg dose of resmetirom were superior to placebo with respect to NASH resolution and improvement in liver fibrosis by at least one stage.
Vitamin B12 and folic acid were found to significantly impact nonalcoholic steatohepatitis (NASH), for which there is no pharmaceutical treatment option
NASH is the second stage of nonalcoholic fatty liver disease (NAFLD); a few potential causes of which include consuming high fructose corn syrup, low-level exposure to glyphosate or choline deficiency
Although NAFLD may have no symptoms it can progress to NASH, fibrosis and finally cirrhosis, with a higher risk of liver cancer. Supplementation with B12 and folic acid appeared to slow the progression of NASH and reverse fibrotic tissue changes in the liver
Iron overload is also associated with liver damage and high iron levels are found in individuals with alcoholic liver disease and NAFLD
Consider protecting your liver by eliminating high-fructose corn syrup from your diet, don’t use Roundup, and make sure to purchase organic, non-GMO produce. Also, take care to get enough B vitamins and choline from your food.
According to the American Liver Foundation,1 approximately 100 million people in the U.S. have nonalcoholic fatty liver disease (NAFLD). Research2 published by Duke-NUS Medical School3 revealed that two B vitamins may have a significant effect on an advanced form of the disease, for which there is no pharmaceutical treatment.4
Your liver weighs just over 3 pounds and is located on the right side of your abdomen, protected by your rib cage.5 It’s the largest solid organ in your body and one of the largest glands, carrying out over 500 essential tasks to maintain optimal health.6
The liver has two main lobes and each of those has eight segments. Every segment is made up of approximately 1,000 lobules that are connected to small ducts. The liver filters your blood, regulates many chemical levels and excretes bile into your intestines to help break down fat. The liver also produces cholesterol, stores and releases glucose and regulates blood clotting.7 Each of these vital functions is impacted by the four stages of NAFLD.
NAFLD is a serious liver condition caused by excess fat in the liver, and not from being exposed to alcohol. The medical term is hepatic steatosis, and it is the most common chronic liver disease in developed countries.8 In one population-based study,9 18.9% of the participants had confirmed NAFLD, which was more prevalent in men than women.
Risk factors in this study were being over age 40, male, and being diagnosed with central obesity and elevated fasting blood sugar, aspartate transaminase (AST) and alanine transaminase (ALT). Dietary fructose is a significant link in the development of NAFLD,10,11,12 chronic hepatic inflammation and an increased risk of developing the next stage of liver disease, nonalcoholic steatohepatitis (NASH).
The results of one study13 presented at the 2022 Endocrine Society annual meeting found a significant link between those whose diet contained the most fructose and the development of NAFLD. In a press release, one researcher on the study, Dr. Theodore Friedman from Charles R. Drew University, said:14
“We found that when adjusting for the demographics and behavioral factors (smoking, modest alcohol consumption, diet quality and physical activity), high fructose consumption was associated with a higher chance of NAFLD among the total population and Mexican Americans.”
Vitamin B12 and Folic Acid May Reverse NASH
The researchers in the featured study15 were studying the effect that vitamins B12 and B9 might have on NASH. After years of inflammation from NAFLD and fatty deposits on the liver, it is possible to develop NASH.16
Dr. Madhulika Tripathi, a senior research fellow with the Laboratory of Hormonal Regulation at Duke-NUS’ Cardiovascular & Metabolic Program, said in a press release,17 “While fat deposition in the liver is reversible in its early stages, its progression to NASH causes liver dysfunction, cirrhosis and increases the risk for liver cancer.”
The researchers were seeking to understand the relationship between hyperhomocysteinemia and NASH.18 Using an animal model, they administered vitamin B12 and folic acid, attempting to reverse the cellular features of NASH. While evaluating preclinical models,19 they discovered that homocysteine attaches to a protein called syntaxin 17 and blocks the protein. This in turn appears to induce the development and progression of NASH.
However, when mice were supplemented with vitamin B12 and folic acid, the levels of syntaxin 17 rose, which slowed the progression of NASH and reversed fibrosis. One of the scientists in the study, Dr. Brijesh Singh, said:20
“Our findings are both exciting and important because they suggest that a relatively inexpensive therapy, vitamin B12 and folic acid, could be used to prevent and/or delay the progression of NASH. Additionally, serum and hepatic homocysteine levels could serve as a biomarker for NASH severity.”
The researchers were excited by the possibilities since the early stages of NAFLD often have no symptoms and don’t usually cause any harm.21 Yet, without identification, the condition can progress to NASH or fibrosis. This can lead to extreme tiredness, unexplained weight loss and weakness.
There are four stages of NAFLD which begin with simple fatty liver steatosis.22 This can progress to NASH, then fibrosis and finally cirrhosis. In the latter stages, patients are also at higher risk for liver cancer.23 During all stages of NAFLD, a person has a higher risk of developing cardiovascular diseases.
Vitamin B12 and Choline Deficiencies?
One reason there is such a high prevalence of individuals with NAFLD and NASH may be a deficiency or insufficiency in Vitamin B12, folic acid and/or choline. According to the National Institute of Diabetes and Digestive and Kidney Diseases,24 NAFLD is more common in individuals who are obese or have obesity-related conditions, such as Type 2 diabetes.
The National Institutes of Health25 reports that the rate of vitamin B12 deficiency is close to 20% in those who are older than 60. This data is from the National Health and Nutrition Examination Survey (NHANES) from 2015 to 2016. Data from another large, nationally representative sample26 demonstrated that serum levels of B12 are inversely associated with obesity.
In other words, people who are obese have a higher risk of NAFLD. A vitamin B12 deficiency may allow NASH to progress and the rate of vitamin B12 deficiency is close to 20% in those older than 60 and higher in those who are obese.
Vitamin B12 is also called cobalamin.27 It’s found in animal food and is a key component in the function and development of the central nervous system. A second essential nutrient for human health that is also associated with central nervous system health and the risk of NAFLD is choline. Choline was identified in 186228 and officially recognized as an essential nutrient by the Institute of Medicine in 1998.29
Choline plays a significant role in human health, from neurotransmitter synthesis to cell structures and has a large impact on the development of NAFLD, atherosclerosis30 and neurological disorders.31 The body can produce some choline endogenously in the liver but not enough to meet human needs. There is an interrelationship between folic acid and choline deficiencies as both are methyl donors.32
When the diet is deficient in folic acid, choline becomes the primary methyl donor, creating greater insufficiency or deficiency of the nutrient. Nearly 12 years ago,33 Chris Masterjohn, who has a Ph.D. in nutritional science, wrote that choline insufficiency or deficiency may play a more significant role in the development of fatty liver disease than fructose.
According to Masterjohn,34 your body uses choline to rid itself of excess fat. Without enough choline, it can trigger fatty liver. Yet, the most significant culprit remains excessive fructose, as it must be metabolized by the liver and is primarily converted into body fat as opposed to being used for energy like glucose. Without enough choline, the fat is deposited in the liver.
The Importance of Iron Levels for Liver Health
Another factor that is associated with liver damage is iron overload. Iron may be one of the most common nutritional supplements that can be found as a single supplement or added to multivitamins and processed foods. However, damage from too much iron may be greater than that from iron deficiency anemia.35
Although it is necessary for biological functions, too much can do tremendous damage. Nearly all adult men and postmenopausal women are at risk for iron overload since there are no efficient means for the body to excrete excess iron. In other words, these populations do not lose blood on a regular basis.
Blood loss is a primary way to lower excess amounts of iron which, if left untreated, can contribute to neurodegenerative diseases, diabetes, heart disease and cancer. Additionally, high iron levels are found in individuals with alcoholic liver disease and NAFLD.36
Low-Levels of Roundup Exposure Damage the Liver
Glyphosate, which is the active ingredient in the herbicide Roundup, is also linked to NAFLD and NASH. Researchers37 from the University of California San Diego School of Medicine38 found patients with NASH had higher residues of glyphosate in their urine, an association that held true regardless of other factors in liver health, such as body mass index, diabetes, age or race.
Exposure to glyphosate may lead to more severe forms of liver disease, and subsequently an increased risk of liver cirrhosis, liver cancer and higher mortality rates than the general population from liver-related and non-liver-related causes.39
In a UC San Diego news release, study researcher Paul J. Mills, Ph.D., explained, “There have been a handful of studies, all of which we cited in our paper, where animals either were or weren’t fed Roundup or glyphosate directly, and they all point to the same thing: the development of liver pathology. So, I naturally thought: ‘Well, could it be exposure to this same herbicide that is driving liver disease in the U.S.?’”40
Glyphosate is also known to trigger the production of reactive oxygen species, leading to oxidative stress. As noted in Scientific Reports, “Elevation in oxidative stress markers is detected in rat liver and kidney after subchronic exposure to GBH [glyphosate-based herbicides] at the United States’ permitted glyphosate concentration of 700 μg/L in drinking water.”41
Researchers from King’s College London also showed an “ultra-low dose” of glyphosate-based herbicides was damaging.42 The study involved glyphosate exposures of 4 nanograms per kilogram of body weight per day, which is 75,000 and 437,500 times below EU and U.S. permitted levels, respectively.43
After a two-year period, female rats showed signs of liver damage, specifically NAFLD and progression to NASH. The researchers noted44 that glyphosate may bring about toxic effects via different mechanisms, depending on the level of exposure, including possibly mimicking estrogen and interfering with mitochondrial function.
Consider These Tips for Liver Support
There are several steps you can take to protect your liver. Among those are eliminating high-fructose corn syrup from your diet, not using Roundup or other glyphosate-based herbicides in your garden, purchasing organic, non-GMO produce and foods, lowering your risk of iron overload and taking care to ensure you get enough B vitamins and choline.
However, we would need to live in a perfect world to ensure our liver is not inundated with a ubiquitous chemical assault commonly found in our industrialized world. As the featured research pointed out, even those with NASH, an advanced form of NAFLD, can benefit from supplementing with vitamins B12 and folic acid.
While the focus of the featured study was NAFLD, overconsumption of alcohol also drives liver damage, cirrhosis and death. Data45 gathered between 1999 and 2016 revealed a 65% increase in annual deaths from cirrhosis, with 25- to 34-year-olds experiencing the greatest relative increase in mortality driven entirely by alcohol-related disease.
Milk thistle is an herb that has been used for thousands of years to support liver, kidney and gallbladder health. In modern times, silymarin, the active ingredient in milk thistle, has been used to treat alcoholic liver disease and hepatitis.46 Silymarin may help suppress cellular inflammation47 and inhibit the mammalian target of rapamycin (mTOR), a pathway that, when overactivated, increases your risk of cancer.48
Coenzyme Q10 (CoQ10) is the third-most consumed supplement,49 yet many people don’t realize how clinically effective it is, including the role it plays to protect your liver. In one study,50 44 patients were divided into two groups. One group was given 100 mg of CoQ10 each day, while the other was given a placebo.
After four weeks, the group taking CoQ10 dropped weight and had lower levels of serum AST, a blood marker that indicates liver disease and/or damage. The reduced version of CoQ10 is ubiquinol. As you age, the body’s ability to absorb and utilize CoQ10 drops, but it can still use ubiquinol.51 Ubiquinol is absorbed three to four times better than CoQ10.52
N-acetylcysteine (NAC) is a precursor needed to produce glutathione, also called the “master antioxidant.”53 NAC helps support liver health in those with hepatitis C and other chronic liver diseases.54
An animal study showed NAC could effectively minimize damage associated with alcohol consumption55 and is used as an antidote for acetaminophen toxicity, which causes liver damage by depleting glutathione.56,57 Research published in Hepatitis Monthly58 has also shown NAC supplementation helps improve liver function in patients with NASH.
The incidence of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis continues to rise with obesity and type 2 diabetes, and all clinicians must screen patients at high cardiometabolic risk, according to a speaker.
Approximately 30% to 37% of U.S. adults have nonalcoholic fatty liver disease, known as NAFLD, and about 8-12% have nonalcoholic steatohepatitis (NASH), which leads to fibrosis and liver failure and a leading indication for liver transplant, Christos S. Mantzoros, MD, DSc, PhD, professor of medicine at Harvard Medical School and chief of endocrinology at VA Boston Healthcare System, said during a presentation at the Heart in Diabetes CME Conference. Often such patients are not diagnosed until serious liver or cardiometabolic complications develop, Mantzoros said.
Mantzoros is a professor of medicine at Harvard Medical School and chief of endocrinology at VA Boston Healthcare System.
“In our society, as the prevalence of obesity goes up, the prevalence of type 2 diabetes goes up, and the prevalence of NAFLD and steatosis goes up,” Mantzoros said. “The NASH epidemic is part of a cardiometabolic disease group. All of us need to be vigilant to make the diagnosis and to prevent and treat it. All of us need to apply all of the tools we have when we make the diagnosis.”
In the U.S., about 7 in 10 people with diabetes will have NAFLD, Mantzoros said, whereas up to 80% of people with NASH will have metabolic syndrome, leading to type 2 diabetes over time. Additionally, these risk factors lead to cardiovascular morbidity and mortality, he said.
“NAFLD and NASH are common, especially among people with obesity, diabetes and metabolic syndrome, and unfortunately most of the time it remains undiagnosed,” Mantzoros told Healio. “We need to think about it, screen and treat it.”
Strategies to treat NAFLD, prevent NASH
There are currently no FDA-approved therapies specifically for NASH; however, Mantzoros highlighted several strategies that can reduce fat in the liver and inflammation:
Weight loss is associated with mild to moderate improvement in NASH, though maintaining weight loss is very challenging, Mantzoros said. The Mediterranean diet is inversely associated with liver steatosis and decreases 10-year CV risk in NAFLD, according to evidence from the ATTICA prospective cohort study recently published in Clinical Nutrition. “In a meta-analysis we put together, we do know that if we follow a Mediterranean diet or Dietary Approaches to Stop Hypertension (DASH) diet, lowering total fat or saturated fat — even if high in monounsaturated fat — we decreased risk for NAFLD and CVD,” Mantzoros said. Similar outcomes are expected in response to the DASH diet.
Bariatric surgery and endoscopic devices have demonstrated improvement in NASH and metabolic syndrome, but evidence for fibrosis improvement is limited, Mantzoros said. “We know from several studies that if we decrease weight by 10% for 1 year, there is NASH resolution in more than 90% of the cases, fibrosis regression in 80% and steatosis improvement in 100% of cases,” Mantzoros said. “Today, we can do this only with bariatric surgery. In the future, we hope we will be able to do this with new anti-obesity drugs.”
Irrespective of the statin used, data show improvements with statin therapy in lipid levels and inflammation, as well as an improvement in NAFLD and NASH. “In an editorial we recently published in Metabolism, we recommend that patients continue statin therapies, unless one has late stage of the disease,” Mantzoros said. “Statins should not be discontinued.”
Some diabetes therapies show promise. Pioglitazone improves liver histology in patients with and without type 2 diabetes with biopsy-proven NASH, and may be used to treat those patients, Mantzoros said. Currently, it is premature to consider GLP-1 receptor agonists or SGLT2 inhibitors to specifically treat liver disease in people with NAFLD or NASH, though data shows the agents can lead to weight loss and decrease steatosis. “They do not improve fibrosis to the degree that we want,” Mantzoros said. “We need larger, longer studies with stronger GLP-1 analogues or combination therapies.”
“When adipose tissue storage is exceeded, triglycerides will be stored in muscle and the liver and this leads to insulin resistance, metabolic syndrome, and not only CVD, chronic kidney disease or diabetes, but also NAFLD,” Mantzoros said. “In addition to lifestyle intervention, many of the same medications [used in diabetes] are expected to be used to treat NAFLD.”
A call to action
As Healio previously reported, eight professional societies issued a joint report on the dangers associated with NAFLD and NASH in July, calling on clinicians to work together across specialties and align treatment strategies.
“We need to realize that this is not a disease only for hepatologists,” Mantzoros said. “Cardiometabolic experts, endocrinologists and primary care physicians need to focus on this epidemic along with nutritionists and exercise physiologists. So many patients who come to our offices go unrecognized.”
Mantzoros said patients must be screened for NAFLD and NASH at the primary care level and diagnosed early to avoid serious complications. Similarly, the joint report also notes that most patients with NAFLD — and many with NASH — have a low risk for clinically significant fibrosis and should be managed by primary care providers.
“We must optimize management with the tools that we have at our disposal today,” Mantzoros said. “Industry and academia need to work together on improving new treatments for this metabolic disorder. There is more coming soon from our working group in terms of recommendations, algorithms, and pathways to follow.”
Nonalcoholic steatohepatitis is the second leading indication for liver transplantation in the United States but there are currently no FDA-approved treatments available.
Rohit Loomba, MD, MHSc, director of the NAFLD Research Center and director of hepatology, professor of medicine at the University of California, San Diego, told Healio Gastroenterology that in the next decade NASH will likely become the No. 1 indication for liver transplantation. The increase in the prevalence and incidence of obesity and type 2 diabetes will increase the burden of liver disease in the coming decades.
NASH is the leading indication for liver transplantation, according to Rohit Loomba, MD, MHSc, director of the NAFLD Research Center and director of hepatology, professor of medicine at the University of California, San Diego. Source: Rohit Loomba, MD, MHSc.
In an interview, Zobair M. Younossi, MD, MPH, FACP, FACG, AGAF, FAASLD, president of Inova medicine, at the Inova Health System and professor and chairman of the department of medicine at Inova Fairfax Medical Campus, said the most challenging part is the lack of awareness about this liver disease.
“There is a tremendous lack of awareness about NAFLD and NASH amongst all stakeholders. That includes patients and providers,” Younossi said. “So there has to be a great deal of focus on understanding this important liver disease that impacts not only clinical outcomes, but also quality of life and we need to make sure that we address that.”
Younossi said there needs to be a better way to identify patients at risk for significant liver disease to give them proper care.
“We have recently completed a global survey of over 3,000 providers like primary care, endocrinologists, gastroenterologists and hepatologists. The data suggested a lack of awareness among front line providers who see most of these patients and a lot of these patients are not getting identified in clinical practices,” Younossi said.
He also said another challenge is conducting risk stratification using noninvasive tests and linking patients at high risk to gastrointestinal and hepatology care.
Zobair M. Younossi
COVID-19 seems more aggressive in patients with visceral obesity, especially morbid obesity, Younossi said, and these poor outcomes may be seen in patients with NAFLD and NASH.
“[The] pandemic had slowed down enrollment of NASH patients in clinical trials of new drugs, initially, but people have actually gone into alternative ways of collecting data, including virtual visits and other novel approaches to clinical trials so it’s not as bad as we initially thought it could be,” he said.
“When I talk to companies, there has obviously been some delays in enrollment [in trials], but I wouldn’t say it’s been catastrophic at all; in fact, for the most part, it’s better than what one might have expected,” Scott Friedman, MD, dean for therapeutic discovery and chief of the division of liver disease at the Icahn School of Medicine at Mount Sinai, told Healio Gastroenterology.
Noninvasive Diagnostics for NAFLD, NASH
Michael W. Fried, MD, FAASLD, chief medical officer of TARGET RWE, told Healio Gastroenterology, liver biopsy was relied on the most for diagnosing and staging NASH; however, he said in usual practice it is not practical to perform biopsy on every patient. Biopsies may be expensive, have modest risk and patients may not accept them. Therefore, it is not the ideal way to diagnose patients, according to Fried.
Michael W. Fried
Fried said many tests rely on algorithms using clinical markers routinely obtained during care of patients with NASH such as the NAFLD fibrosis score, which includes age, diabetes, aspartate aminotransferase, alanine aminotransferase platelet count and albumin to create a risk score for likelihood of advanced fibrosis.
Fried said there are some blood tests, but many were not recognized as being the most accurate way to diagnose to NASH.
Friedman told Healio Gastroenterologythe NAFLD fibrosis score uses measurements in blood as well as another blood test from OWL metabolomics that measures lipid components in blood and is undergoing validation.
Fried said his group from TARGET-NASH presented information regarding a few initiatives in which non-invasive markers were associated with long-term outcomes related to liver disease, cardiovascular disease, liver cancer and mortality at the recent AASLD meeting.
“We’re also working to validate a simple clinical algorithm that we use as a pragmatic definition for NASH and compare the results from liver biopsies that have been reviewed by a central pathologist,” Fried said.
Friedman said there is also growing interest in detecting new proteins that may reflect the disease state. Technology that measures many proteins in blood at once like the SomaLogic platform, a newer entry in the NASH diagnostic space, may help.
Friedman also mentioned magnetic resonance elastography, the stiffness test for measuring potential correlation with fibrosis. A related technology, corrected T1 weighted imaging, is being evaluated by Perspectum Diagnostics, a company in the U.K.
Scott Friedman
“I work with Glympse Bio, and they use a test that administers nanoparticles that are cleaved in a very selective way and excreted in the urine where they can be measured, and the pattern of the particles’ breakdown products in the urine may reflect the stage of disease – this is also nearing clinical testing,” Friedman said.
He also said there are at least four companies using artificial intelligence-based digital pathology methods to quantify the different features of a liver biopsy. These methods do not rely upon the evaluation of pathologists or may complement them, since a pathologist’s evaluation is more subjective. Among these companies are Histo Index, Pharma Net, Path AI and Revealbio.
“As an endocrinologist, I see patients with obesity in combination with type 2 diabetes, so you know one of the things I’m always looking for is whether those patients have evidence of NASH,” Peter Goulden, MD, FRCP, medical director, endocrinology, Mount Sinai, told Healio. “So, one of the noninvasive measures that I will look at to determine that is if they had a recent liver enzyme test. You may see elevation on some of the liver enzymes, particularly the AST, ALT, gamma-GT, three of the enzymes we see. But that’s not always the case in NASH.”
He said liver ultrasounds can indicate if there is NAFLD (NASH is only diagnosed by biopsy). Additionally, transient elastography equipment such as FibroScan (Echosens) and MR elastography can assess liver elasticity as well as fatty liver disease.
Radiologic tests are based on measurement of liver stiffness, but they can also assess the amount of fat in the liver. The most common one used in clinical practices is transient elastography (TE), which is a point of care test that can be used in a clinical setting. According to Younossi, TE is much more practical in the clinical setting. Although MR elastography is the most accurate technology, it is less available and more expensive than TE.
These radiologic tests are used in conjunction with other non-invasive clinical tools for fibrosis such as FIB-4. If the FIB-4 is less than 1.3, it suggests a low risk for significant liver disease or fibrosis. However, if the FIB-4 is more than 1.3, then a second line of noninvasive testing such as TE should be done, according to Younossi.
Loomba and colleagues published study results in Gut that showed MR elastography 3.3 or greater Kpa with FIB-4 1.6 or more had a high positive predictive value of over 90%, which can eliminate the need for liver biopsy in those who are positive in the screen.
Younossi said there are currently no serum biomarkers approved for fibrosis in the U.S.; however, in Europe there is the alpha test or enhanced liver fibrosis test that determines the stage of liver disease.
“In the future, there’s going to be much better use of these algorithms that risk stratify patients. Probably in the medium term, we will have additional algorithms that will be much more accurate to not only rule out significant liver fibrosis, but also rule in presence of advanced fibrosis,” Younossi said.
“In the future, there’s going to be much better use of these algorithms that risk stratify patients. Probably in the medium term, we will have additional algorithms that will be much more accurate to not only rule out significant fibrosis, which each can be pretty good, but also rule in significant fibrosis, which is what we are hoping that the future noninvasive tests will optimized,” Younossi said.
“We are moving toward a future where we will not need a liver biopsy,” Loomba said. “Currently, for treatment trials, we are using some of these tests to [identify] who should get a biopsy rather than everybody coming in getting a biopsy.”
“Everybody recognizes that right now the lack of good noninvasive markers, certainly markers that can be used for drug approval in the phase 3 trial, is a huge handicap to progress in drug approval,” Friedman said.
Pipeline of Treatments
“The NASH therapeutic pipeline is really robust and, truly there are probably dozens of medications with different mechanisms that are being investigated in various phases of drug development,” Fried said. “But, while there have been some setbacks, there are also numerous drugs, particularly some presented at the Liver Meeting Digital Experience just a few weeks ago, that are showing great promise for the potential to treat NASH. Most of these drugs are going to be approved on the basis of relatively short-term studies demonstrating histological improvement and ameliorating histological changes in NASH.”
Younossi said right now lifestyle modification is the best treatment option available for NAFLD and NASH. However, he said to get the benefit of the weight loss and lifestyle modification, patients would have to lose 10% of their baseline weight, which is both difficult to achieve and maintain in the long term.
Younossi said vitamin E is not FDA approved but is recommended by AASLD guidance for non-diabetic patients with NASH and no cirrhosis.
Peter Goulden
“The first thing I really want to emphasize before I even talk about medication is lifestyle, right at the start with these cases,” Goulden said. “We know that actually that’s probably one of the most effective ways of treating this, so actually it may be somewhere between 5% and 10% weight loss, emphasizing dietary changes, steady weight loss, physical activity; there’s good evidence around that.”
Goulden said as an endocrinologist he tends to look for treatments that he may use in patients with type 2 diabetes. He said he has used a glucagon-like peptide-1 (GLP-1) receptor antagonist that produces weight loss and there are improvements in liver enzymes. He also uses metformin and sodium-glucose cotransporter-2 inhibitors in patients with type 2 diabetes.
Loomba said we have FXRs such as obeticholic acid (Intercept Therapeutics Inc). Intercept showed positive data, Friedman said. However, the FDA cancelled the advisory board to consider approving the drug because of safety concerns that are being addressed by the company. Agonists may also be effective.
“We also have therapies that lower liver fat and could reduce lipotoxicity. Among those, we have [acetyl-CoA carboxylase (ACC)] inhibitor, and I have designed and published several of those trials,” Loomba said.
Loomba said he and his colleagues combined a low-dose FXR with a full-dose ACC inhibitor and showed that it can improve liver histology in patients with stage 3 and stage 4 cirrhosis.
Friedman also pointed out that there are other FXR agonists such as tropifexor (Novartis) and cilofexor (Gilead).
Thyroid hormone beta receptor agonists – which increase fatty acid oxidation in the liver, reduce liver fat and improve liver disease – can improve NASH resolution. Among these, resmetirom from Madrigal is the most advanced of these agents. Further, researchers are conducting clinical trials of BK2809 from Viking Therapeutics in patients with biopsy-proven NASH. Loomba said there are robust data from these trials showing liver fat reduction.
Loomba noted there are a few therapies in the fibroblast growth factors (FGF) family such as FGF21 that can reduce liver fat and improve lipotoxicity. It may also improve insulin resistance at the level of the liver and thus improve NASH. Additionally, FGF19 may inhibit bile acid synthesis, decrease lipotoxicity, increase beta oxidation and decrease fatty acid synthesis.
“There’s a study that GLP-1 with ACC inhibitor achieves better reduction in liver fat and you could see greater reduction in ALT and AST, a biomarker based study, so I expect in the future there will be combination therapy trial,” Loomba said.
TVB-2640 from Sagimet Biosciences is a fatty acid synthase inhibitor that can lead to reduction in de novo lipogenesis, reduction in liver fat, improvement in ALT and AST and other biomarkers of fibrosis and leads to significant reduction in liver fat with an oral dose of 50 mg daily. These promising data provide proof-of-concept data to move to assess the efficacy of TVB-2640 in patients with biopsy-proven NASH with fibrosis.
“Semaglutide, which is a GLP-1 agonist from Novo Nordisk, yielded a dramatic improvement in the resolution of NASH, however the drug did not improve fibrosis and there was a very high placebo response rate, so it looked encouraging but not definitive and it was a phase 2 not a phase 3 trial,” Friedman said.
“[This is] just the tip of the iceberg, there are so many other things going on in NASH that to me it’s just a matter of time before we break through with the clinical drugs and some hope for patients,” Friedman said.
During the Liver Meeting Digital Experience, Phillip N. Newsome, PhD, from the Birmingham Biomedical Research Centre in the United Kingdom, said semaglutide produces NASH resolution without worsening fibrosis.
Fried said with the TARGET-NASH longitudinal study, patients once treated with new, approved medications in the future are going to be observed to assess long-term safety and effectiveness over multiple years.
“Demonstrating the impact of these medicines over the long term will be really important for the field,” Fried said. “So, we’re very excited by the potential for all these new drugs.”
“We have several classes of agents that are becoming available and moving on to phase 2b and phase 3 trials that show promise, and so the future seems really bright for both monotherapy and then moving on to combination therapy for treatment of NASH and NASH-related fibrosis,” Loomba said.
Younossi said in the future he believes there will be a combination of two or three drugs that will improve fibrosis stage of patients with NASH. Once the initial improvement is documented, patients may be managed with a maintenance regimen to continue to experience the benefits, according to Younossi.
What to Expect in 2021
“In my estimation, hopefully we’ll have a drug approved in 2021, hopefully we’ll have at least one additional serum biomarker available for approval in 2021, but a number of output protocols for new research would be also up and running,” Younossi said.
Friedman said there may not be an approval seen for a NAFLD or NASH treatment in 2021. He said the treatment closest to getting approval may be Intercept’s obeticholic acid, which is working with the FDA to address its concerns.
Loomba said, “Next year in 2021, we’ll have a lot of activity. There will be two or three programs that will get to combination and then we might see some additional results that might show promise and drugs might have a chance for approval.”
Goulden said for now there are currently some treatments for type 2 diabetes and weight loss also helps in combination with physical therapy and diet.
“Actually, there’s some studies showing that resistance exercising [helps] as well,” Goulden said. “There’s some studies that show patients who do regular resistance exercise also can see improvement in their liver function.”
“For the foreseeable future, the treatment of NASH is still going to be focused on maintaining ideal body weight, improved management of underlying metabolic diseases such as diabetes, hyperlipidemia, trying to minimize cardiovascular risk,” Fried said. “It’s a little unclear exactly when these new approved therapeutics will be routinely available for clinical use. But I do expect that the results from these more advanced phase 2 and phase 3 trials that we’re going to start seeing more and more that will provide a lot of insights into the best ways to treat NASH and I’m confident there will be multiple drugs available, ultimately to treat this disease.”
Fried said NASH is a complex, multiorgan disease that may involve different mechanisms of action, so it may be beneficial to have several approved drugs. This way the therapy can be tailored to the individual patient because some patients may respond better to a certain mechanism than others.
“Real world evidence will certainly contribute to the potential to help tailor these medications better as they get out into the marketplace,” Fried said. “Once we start having drugs available in the marketplace is again going to help refine how these medications are used similar to how real-world evidence really helped inform the way we treated hepatitis C in the past.”
“So, there’s a lot of exciting things going on and these kinds of real-world data are going to be very important for many years to come,” Fried said.
“It’s a marathon, not a sprint,” Friedman said. “There’s interest, there’s a rising unmet need, and despite a couple of setbacks in drug approvals, no one is giving up on the space, although investors are getting a little twitchy. But from the point of view of somebody who’s been in the field for a while, I’m still very optimistic in the long term.”
“We’re really starting to wrap our arms around the understanding of the disease in a new way,” Friedman said. “So, while there will not be any overnight success stories, progress will be incremental but meaningful.”
References:
Jung J, et al. Gut. 2020;doi:10.1136/gutjnl-2020-322976.
Semaglutide produces NASH resolution without worsening fibrosis. Available at: www.healio.com. Accessed on: Dec. 20, 2020.
To streamline and validate diagnosis of and clinical trials in nonalcoholic steatohepatitis, one group is on a mission to determine the best noninvasive tests for all physicians to use, according to a presentation.
“As you know, there are many noninvasive tests that are in development, but there are very few that are actually approved for any context of use,” Arun J. Sanyal, MBBS, MD, professor in the department of internal medicine in the division of gastroenterology, hepatology and nutrition at Virginia Commonwealth University School of Medicine, said during The Liver Meeting Digital Experience. “In this cross-sectional analysis of multiple biomarker panels in the same blood sample from a highly phenotyped NAFLD population, multiple biomarkers met a priori criteria for preliminary success. … There was differential performance across biomarkers for both NASH and for fibrosis making it likely that future combinatorial approaches could be used to enhance diagnostic position.”
NIMBLE collaboration
In the NIMBLE collaboration with the NASH Clinical Research Network (CRN), researchers looked at 1,073 preselected patients with NAFLD (n = 220) or NASH (n = 853) distributed across fibrosis stages: F0 (n = 222; mean age, 47.8 years; 44.6% men; 71.2% white), F1 (n = 114; mean age, 48.1 years; 45.6% men; 59.6% white), F2 (n = 262; mean age, 51.7 years; 38.9% men; 76.2% white), F3 (n = 277; mean age, 54.4 years; 32.9% men; 78.9% white) and F4 (n = 198; mean age, 56.2 years; 30.3% men; 86.2% white). They analyzed results from the following tests performed within 90 days of a liver biopsy: NIS4 (Genfit), the Enhanced Liver Fibrosis score (ELF, Siemens Healthineers), FibroMeter VCTE (FM-VCTE, Echosens), PRO-C3 (Nordic Biosciences) and the One-Way Lipidomics (OWL, OWLiver). Each technique was compared to FIB4 and ALT.
“We have to really parse it down very finely to think about whether we are going to use it for diagnosis, to establish prognosis, for monitoring disease, for predicting treatment response. Each one is sort of considered a different context of use and each one has to be evaluated independently,” Sanyal said. “We felt our immediate focus was to try to identify the population that is at risk for having more liver outcomes.”
The NIS4 test met criteria for diagnosis of NASH and NAFLD Activity Score (NAS) of 4 or greater, while NIS4, ELF and FM-VCTE all met criteria for diagnosis of F2 or higher. ELF and FM-VCTE improved for F3 and F4.
In looking for NASH diagnosis, the group showed NIS4 had an area under the curve (AUROC) of 0.832 vs. ALT’s 0.678, positioning it to be accurate (P < .001). Similarly, NIS4 outperformed ALT for the NAFLD activity score with an AUROC of 0.815 vs. ALT’s 0.726 (P < .001).
The OWL liver panel provides results specifically as a yes or no, so Sanyal explained there is no AUROC for this test, but it did provide 63.3 for sensitivity and 75.4 for specificity.
Sanyal showed that the ELF test performed at 0.828 AUROC (P < .001) and “progressively improved” to 0.855 (P < .001) at cirrhosis level, making it superior to both the baseline and FIB4 as its comparator.
PRO-C3 showed to be superior to the unit line but not to FIB4 and “with increasing fibrosis, the performance declined,” Sanyal said.
The FibroMeter VTCE was performed in 393 patients, showing an AUROC from 0.841 to 0.897 as fibrosis progressed, making it superior to the unit line and to FIB4 (all P < .001). Sanyal noted this subset of patients was the only one to have a FibroScan (Echosens) performed within the pre-set time period.
“Lastly, I want to point out that FIB4 also had fairly robust diagnostic characteristics for these fibrosis-related endpoints,” Sanyal said in his presentation.
Next steps
This initial stage of the NIMBLE study laid the groundwork, Sanyal said, by clarifying sensitivity and specificity for this group of who would most benefit from knowing the status of their disease.
“The basis for looking at all of these were really based on panels whose laboratory analytic robustness is already established and meets regulatory standards, so we think when you take the totality of all of this data, we now have made substantial progress toward meeting the evidence burden for biomarker qualification for enrichment of the diagnostic context of use for people who have NASH with significant fibrosis which is stage 2 or higher,” Sanyal said. “We are very excited about these results.”
In stage 2 of NIMBLE, Sanyal said these biomarkers will be integrated with imaging workstreams to address disease monitoring types of use and build to truly predictive models.
“It is time to include the liver as a critical end organ that is associated with type 2 diabetes. Diabetologists are often focused on kidney disease, heart disease, eye disease, etc, but many of these patients, especially those who progress to bridging fibrosis and cirrhosis, will die of their liver disease,” he said. “Since most of those patients have type 2 diabetes, it behooves us now to increase awareness within the diabetes population but coupled with giving them tools to identify this in their routine practice.”
“NIMBLE is an advanced qualification plan. We want something approved that every doctor can use in the next 2 years,” Sanyal said.
The emerging treatment landscape of nonalcoholic steatohepatitis has “exploded” as understanding of the pathogenesis grows, according to a presenter at GUILD 2022.
“We [have] a huge armamentarium of drugs in development,” Manal F. Abdelmalek, MD, MPH, professor of medicine and director of the NAFLD Clinical Research Program at Duke University School of Medicine, told attendees. “In my opinion, the future of NASH is going to be binding combination therapies, for which we have a foundation of anti-metabolic therapy, coupled with anti-inflammatory or anti-fibrotic therapy, depending on where patients are in the disease spectrum.”
Abdelmalek noted that liver directed pharmacotherapy should be reserved for patients with NASH and “significant” fibrosis, and that anti-metabolic therapy will be critical in the treatment of NASH.
According to Abdelmalek, there are several drugs in phase clinical 3 trials, including:
Lanifibranor
Obeticholic acid
Semaglutide
Resmetirom
Among those in phase 2 or phase 2b are:
Aldafermin
Cilofexor
EDP 305
Efruxafermin
EYP001
LMB763
Px-104
89 Bio-100
Tropifexor
VK2809
“There is the potential for an FDA subpart approval of a drug, I believe in the upcoming 1 to 2 years, and combination therapy is anticipated to occur in the future,” Abdelmalek said.
As liver transplants significantly increase among older patients, nonalcoholic steatohepatitis has become the most common reason for the procedure in this population, according to a study published in Hepatology Communications.
“Another study from our team, which in publication in Clinical Gastroenterology and Hepatology, suggests that the proportion of elderly patients in need of liver transplantation in the U.S. is sharply increasing,” study author Zobair M. Younossi MD, MPH, president of Inova Medicine Services and professor and chairman of the department of medicine at Inova Fairfax Medical Campus in Virginia, told Healio. “At present, NASH is the most common indication for liver transplantation among the elderly. The outcomes of these patients have been improving in the past two decades so that three in four [patients] can expect to live at least 5 years posttransplant.” Registry of Transplant Recipients to identify 31,209 LT candidates, aged 65 years or older, to evaluate on-list and posttransplant outcomes. Among the common etiologies were NASH (31%), hepatitis C (23%) and alcohol liver disease (18%). In addition, 30% of candidates had hepatocellular carcinoma.
infographic on NASH rates increasing in older patients According to researchers, the proportion of adult LT candidates 65 years and older significantly increased (P < .0001) from 9% (2002-2005) to 23% (2018-2020); similarly, the proportion of NASH among older patients increased from 13% to 39% during those study periods. Of those, 54% underwent LT.
Results from multivariate analysis indicated that more recent years of listing, older age, male sex, higher Model for End-Stage Liver Disease (MELD) score and HCC (all P < .01) were independent predictors of an increased chance for receiving a transplant in patients 65 years and older.
In addition, posttransplant mortality was higher in older patients compared with younger LT recipients; however, this mortality rate decreased over time. Independent predictors of higher posttransplant mortality in older LT recipients included earlier years of transplantation, older age, male sex, higher MELD score, history of type 2 diabetes, retransplantation and HCC at baseline or follow-up (all P < .01).
“We found that elderly patients in need of a liver transplant are increasingly being considered for the procedure,” Younossi and colleagues concluded. “Further research is
needed to improve both on-list and posttransplant management of patients of advanced age in order to meet the growing demand for this complex treatment among the aging population with liver disease.”
PERSPECTIVE
Jamile’ Wakim-Fleming, MD
Fatty liver disease is rapidly increasing, and rates have doubled in the past 5 years compared with 15 years earlier, for both genders and for all ages. With this increase, a parallel rise in complications has been observed, including liver failure and liver cancer, as well as increased rates of liver transplantations to save life.
The seminal study by Younossi and colleagues looked specifically at LT rates in an older age group, drawing data from the Scientific Registry of Transplant Recipients. More than 31,000 individuals aged 65 years and older, listed for LT between 2002 and 2020, were studied and assessed for frequency of transplant, cause of liver disease and mortality outcomes. Data comparisons were made between earlier listing vs. recent listing.
The authors showed that the proportion of older patients listed for LT is increasing and that the most common cause of their liver disease is fatty liver and liver cancers. They also found that mortality from LT is higher in the older group, but that the mortality rates have been declining over time. Deterioration and removal from the transplant list have increased over time.
Findings from this study are very important and serious, as they demonstrate that more people are affected by fatty liver disease, more people aged 65 years and older need LT and more people are deteriorating and removed from the transplant list.
Knowing that fatty liver is usually a preventable disease and that the health consequences can be dire and costly, one may draw the conclusion that prevention is crucial. We need to prevent the progression of the fatty steatotic livers before complications occur, by increasing awareness of the disease, disseminating education and knowledge among clinicians and the public, and instituting a prompt diagnosis and early intervention.
Jamile’ Wakim-Fleming, MD Director, Fatty Liver Disease Program Digestive Disease & Surgery Institute Cleveland Clinic
“Although generally considered asymptomatic, almost half of patients with NASH have clinically significant fatigue which, in turn, has a profound negative impact on the overall patient experience,” Zobair M. Younossi, MD,MPH, president of Inova Medicine Services and professor and chairman of the department of medicine at Inova Fairfax Medical Campus in Virginia, and colleagues wrote in Clinical Gastroenterology and Hepatology. “In this context, ongoing clinical trials aim at finding a drug-based therapy for NASH that may reverse fibrosis and could also potentially improve fatigue. Given that, patient-reported outcome instruments are now commonly included in these trials in order to provide a comprehensive assessment of the impact of the investigational drugs on patients and their experience.”
For 2 years, Younossi and colleagues followed 1,679 patients with biopsy-confirmed NASH, of whom 802 had bridging fibrosis (F3) and 877 had compensated cirrhosis (F4). Fatigue was quantified at baseline with the seven-point Chronic Liver Disease Questionnaire (CLDQ)- NASH fatigue domain, in which lower scores indicate worse fatigue. Time to liver-related clinical events, such as progression to histologic cirrhosis or hepatic decompensation in F3 or F4, was assessed with Cox proportional hazard model.
At a median follow-up of 16 months, investigators observed 15% (n = 123) of NASH F3 patients experienced liver-related events, mostly in progression to histologic cirrhosis, and 3.5% (n = 31) of NASH F4 patients experienced hepatic decompensation. Among F3 patients, the mean baseline CLDQ-NASH fatigue score was 4.77, with those who experienced liver-related events reporting lower baseline scores of 4.47 compared with 4.83. Among patients with F4, the mean fatigue score was 4.56, and in those who decompensated, the scores at follow-up were 3.74 compared with 4.59.
After adjusting for confounders, researchers observed a significant correlation between lower fatigue scores and risk for liver-related or decompensation events (adjusted HR = 0.85; 95% CI, 0.74-0.97, per 1 point in fatigue score in F3; aHR = 0.62; 95% CI, 0.48-0.81 in F4).
“This suggests that, in addition to commonly used clinical parameters, presence of clinically significant fatigue can identify NASH patients at risk for adverse events,” the authors wrote. “Since fatigue also negatively impacts patients [health-related quality of life] and work productivity, it adds to the disease burden related to NASH. Given the critical importance of fatigue in NASH, clinical trials of regimens for NASH should not only show improvement of surrogates of clinical endpoints, such as the stage of fibrosis or resolution of NASH, but also improvement in patient-reported endpoints, such as fatigue.”
The emerging treatment landscape of nonalcoholic steatohepatitis has “exploded” as understanding of the pathogenesis grows, according to a presenter at GUILD 2022.
“We [have] a huge armamentarium of drugs in development,” Manal F. Abdelmalek, MD, MPH, professor of medicine and director of the NAFLD Clinical Research Program at Duke University School of Medicine, told attendees. “In my opinion, the future of NASH is going to be binding combination therapies, for which we have a foundation of anti-metabolic therapy, coupled with anti-inflammatory or anti-fibrotic therapy, depending on where patients are in the disease spectrum.”
Abdelmalek noted that liver directed pharmacotherapy should be reserved for patients with NASH and “significant” fibrosis, and that anti-metabolic therapy will be critical in the treatment of NASH.
According to Abdelmalek, there are several drugs in phase clinical 3 trials, including:
Lanifibranor
Obeticholic acid
Semaglutide
Resmetirom
Among those in phase 2 or phase 2b are:
Aldafermin
Cilofexor
EDP 305
Efruxafermin
EYP001
LMB763
Px-104
89 Bio-100
Tropifexor
VK2809
“There is the potential for an FDA subpart approval of a drug, I believe in the upcoming 1 to 2 years, and combination therapy is anticipated to occur in the future,” Abdelmalek said.
As liver transplants significantly increase among older patients, nonalcoholic steatohepatitis has become the most common reason for the procedure in this population, according to a study published in Hepatology Communications.
“Another study from our team, which in publication in Clinical Gastroenterology and Hepatology, suggests that the proportion of elderly patients in need of liver transplantation in the U.S. is sharply increasing,” study author Zobair M. Younossi MD, MPH, president of Inova Medicine Services and professor and chairman of the department of medicine at Inova Fairfax Medical Campus in Virginia, told Healio. “At present, NASH is the most common indication for liver transplantation among the elderly. The outcomes of these patients have been improving in the past two decades so that three in four [patients] can expect to live at least 5 years posttransplant.” Registry of Transplant Recipients to identify 31,209 LT candidates, aged 65 years or older, to evaluate on-list and posttransplant outcomes. Among the common etiologies were NASH (31%), hepatitis C (23%) and alcohol liver disease (18%). In addition, 30% of candidates had hepatocellular carcinoma.
According to researchers, the proportion of adult LT candidates 65 years and older significantly increased (P < .0001) from 9% (2002-2005) to 23% (2018-2020); similarly, the proportion of NASH among older patients increased from 13% to 39% during those study periods. Of those, 54% underwent LT.
Results from multivariate analysis indicated that more recent years of listing, older age, male sex, higher Model for End-Stage Liver Disease (MELD) score and HCC (all P< .01) were independent predictors of an increased chance for receiving a transplant in patients 65 years and older.
In addition, posttransplant mortality was higher in older patients compared with younger LT recipients; however, this mortality rate decreased over time. Independent predictors of higher posttransplant mortality in older LT recipients included earlier years of transplantation, older age, male sex, higher MELD score, history of type 2 diabetes, retransplantation and HCC at baseline or follow-up (all P < .01).
“We found that elderly patients in need of a liver transplant are increasingly being considered for the procedure,” Younossi and colleagues concluded. “Further research is
needed to improve both on-list and posttransplant management of patients of advanced age in order to meet the growing demand for this complex treatment among the aging population with liver disease.”
PERSPECTIVE
Jamile’ Wakim-Fleming, MD
Fatty liver disease is rapidly increasing, and rates have doubled in the past 5 years compared with 15 years earlier, for both genders and for all ages. With this increase, a parallel rise in complications has been observed, including liver failure and liver cancer, as well as increased rates of liver transplantations to save life.
The seminal study by Younossi and colleagues looked specifically at LT rates in an older age group, drawing data from the Scientific Registry of Transplant Recipients. More than 31,000 individuals aged 65 years and older, listed for LT between 2002 and 2020, were studied and assessed for frequency of transplant, cause of liver disease and mortality outcomes. Data comparisons were made between earlier listing vs. recent listing.
The authors showed that the proportion of older patients listed for LT is increasing and that the most common cause of their liver disease is fatty liver and liver cancers. They also found that mortality from LT is higher in the older group, but that the mortality rates have been declining over time. Deterioration and removal from the transplant list have increased over time.
Findings from this study are very important and serious, as they demonstrate that more people are affected by fatty liver disease, more people aged 65 years and older need LT and more people are deteriorating and removed from the transplant list.
Knowing that fatty liver is usually a preventable disease and that the health consequences can be dire and costly, one may draw the conclusion that prevention is crucial. We need to prevent the progression of the fatty steatotic livers before complications occur, by increasing awareness of the disease, disseminating education and knowledge among clinicians and the public, and instituting a prompt diagnosis and early intervention.
ARYAN'S BLOG 