To provide evidence-based recommendations regarding the diagnosis and management of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) to endocrinologists, primary care clinicians, health care professionals, and other stakeholders.
Methods
The American Association of Clinical Endocrinology conducted literature searches for relevant articles published from January 1, 2010, to November 15, 2021. A task force of medical experts developed evidence-based guideline recommendations based on a review of clinical evidence, expertise, and informal consensus, according to established American Association of Clinical Endocrinology protocol for guideline development.
Recommendation Summary
This guideline includes 34 evidence-based clinical practice recommendations for the diagnosis and management of persons with NAFLD and/or NASH and contains 385 citations that inform the evidence base.
Conclusion
NAFLD is a major public health problem that will only worsen in the future, as it is closely linked to the epidemics of obesity and type 2 diabetes mellitus. Given this link, endocrinologists and primary care physicians are in an ideal position to identify persons at risk on to prevent the development of cirrhosis and comorbidities. While no U.S. Food and Drug Administration-approved medications to treat NAFLD are currently available, management can include lifestyle changes that promote an energy deficit leading to weight loss; consideration of weight loss medications, particularly glucagon-like peptide-1 receptor agonists; and bariatric surgery, for persons who have obesity, as well as some diabetes medications, such as pioglitazone and glucagon-like peptide-1 receptor agonists, for those with type 2 diabetes mellitus and NASH. Management should also promote cardiometabolic health and reduce the increased cardiovascular risk associated with this complex disease.
Conclusions
Endocrinologists and primary care clinicians are in an ideal position to identify those at risk early on to prevent the development of cirrhosis and comorbidities. Screening should involve calculation of the individual’s liver fibrosis risk (FIB-4), followed by additional plasma biomarkers and/or liver imaging based on fibrosis risk stratification into low, indeterminate, or high risk of developing future cirrhosis, with referral to a liver specialist for those in the higher-risk groups. Lifestyle changes leading to an energy deficit if overweight or obese and improved cardiometabolic health are essential to reduce CVD risk. Treatment must include consideration of weight-loss medications, particularly GLP-1 RAs with proven benefit for steatohepatitis and bariatric surgery. Some diabetes medications, such as pioglitazone and GLP-1 RAs, should be preferred for those with T2D and NASH, particularly when at indeterminate or high risk of developing future cirrhosis. Management should also include careful control of CV risk factors, such as hypertension and atherogenic dyslipidemia. Pediatric NAFLD is also becoming a growing concern, but there is limited awareness among health care professionals about the problem. Inadequate evidence in terms of the optimal diagnostic and treatment pathways is a major barrier with current care being based on early diagnosis and promotion of healthy lifestyle changes. Rapid changes in diagnostic tools and in drug development promise to offer new options for endocrinologists and other health care professionals involved in the management of NAFLD.
There is still paucity on the effects of dietary and supplemental fatty acid on non-alcoholic fatty liver disease (NAFLD). The aim of this review is to systematically review and summarise the effect of fatty acids intake on liver-related outcomes in adult patients with NAFLD.
Methods
The review was conducted using Cochrane CENTRAL Library, Scopus, Embase, MEDLINE, PubMed, and Web of Science. A total of 2786 records were identified, and of these, 36 studies (31 were randomised control trials (RCTs), and 5 were case-control studies) were included. Quality assessment was conducted using the Revised Cochrane Risk of Bias tool and Joanna Briggs Institute checklists.
Results
Of 36 articles, 79% of RCTs and 66% of case-control studies had a low risk of bias. Potential heterogeneity has been observed in assessment of liver-related outcomes. According to the RCTs, there was moderate evidence (3/6 studies) that a diet characterised by a high MUFA, PUFA and low SFA showed reduced liver fat and stiffness. The using of culinary fats that are high in MUFA (4/6 studies) reduces liver steatosis. n-3 PUFA supplementation in combination with a hypocaloric or heart healthy diet with a low SFA improved liver enzyme level (5/14 studies) and steatosis score (3/14 studies).
Conclusions
Effects on NAFLD parameters, including liver fat content (assessed via magnetic resonance imaging/spectroscopy), stiffness and steatosis score (assessed by ultrasonography), were primarily related to fatty acid composition independent of energy intake. Further investigation is needed to determine the mechanism of specific fatty acid on the accumulation of liver fat.
Physically active patients with nonalcoholic fatty liver disease were more likely to achieve at least a 30% reduction in MRI-measured liver fat, according to research in The American Journal of Gastroenterology.
“In the absence of a regulatory agency-approved drug treatment or a cure, lifestyle modification with dietary change and increased exercise is recommended for all patients with NAFLD,” Jonathan G. Stine, MD, MSc, director of the fatty liver program and associate professor of medicine and public health sciences at Penn State Health, told Healio.
“With that said, there are many key unanswered questions about how to best prescribe exercise as medicine to our patients with NAFLD, including whether the liver-specific benefit of exercise can be seen without body weight loss and if found, what dose of exercise is required in order to achieve clinically meaningful benefit.”
In a systematic review and meta-analysis, Stine and colleagues examined the association between exercise training (defined as a type of physical activity which is planned, structured, repetitive and intended to improve or maintain physical fitness) and reduction in MRI-measured liver fat (30% relative reduction). They also compared the impact of different exercise doses on absolute and relative change in liver fat.
The final analysis included 14 studies, comprised of 551 patients with NAFLD (mean age, 53.3 years; 47% women; mean BMI 31.3 kg/m2).
Seven studies (152 patients) were used in the analysis of the primary outcome. The pooled rate of at least a 30% relative reduction in MRI-measured liver fat was 34% among patients in the exercise training group vs. 13% among patients in the control group. Further, exercise training correlated with an increased likelihood of achieving this reduction (pooled OR = 3.51; 95% CI, 1.49-8.23).
In an analysis of 14 studies for the secondary outcomes, the mean change in absolute liver fat was –6.7% and –0.8% for exercise and control groups, respectively (pooled mean difference = –5.8%; 95% CI, –8.1 to –3.6). Nine studies were analyzed to determine the mean relative change in liver fat of –24.1% vs. 7.3% (–26.4%; 95% CI, –47.2 to –5.5). Further, an exercise dose of at least 750 metabolic equivalents of task minutes per week, such as 150 minutes of brisk walking, led to a greater reduction in liver fat (OR = 3.73; 95% CI, 1.34-10.41) compared with lesser doses of exercise.
Researchers also noted treatment response was independent of “clinically significant” body weight loss of 5% or more.
“Our work highlights a novel way to approach this important topic by suggesting that the goal of exercise training in patients with NAFLD should no longer be to lose body weight, but rather to improve their NAFLD, physical fitness and overall health,” Stine said.
However, he noted further research is needed to investigate mechanisms underlying the benefit of exercise, understand and develop the best tools to effectively screen and assess a patient for NAFLD prior to starting an exercise program, and determine optimal exercise prescriptions for potential improvement of other health outcomes.
“We also need to determine how to best incorporate collaboration with an exercise specialist into the routine clinical care of patients with NAFLD,” Stine said.
Using single-nuclear sequencing of mice and human liver tissue and advanced 3D glass imaging of mice to characterize key scar-producing liver cells—researchers at the Icahn School of Medicine at Mount Sinai have uncovered novel candidate drug targets for non-alcoholic fatty liver disease (NAFLD).
“Advanced hepatic fibrosis, driven by the activation of hepatic stellate cells (HSCs), affects millions worldwide and is the strongest predictor of mortality in nonalcoholic steatohepatitis (NASH); however, there are no approved antifibrotic therapies,” wrote the researchers. “To identify antifibrotic drug targets, we integrated progressive transcriptomic and morphological responses that accompany HSC activation in advanced disease using single-nucleus RNA sequencing and tissue clearing in a robust murine NASH model.”
The researchers performed single-nuclear sequencing in parallel studies of both mouse models of NASH and human liver tissue from nine subjects with NASH and two controls. They identified a shared number of 68 pairs of potential drug targets across the two species.
“We aimed to understand the basis of this fibrotic scarring and identify drug targets that could lead to new treatments for advanced NASH by studying hepatic stellate cells, which are the key scar-producing cells in the liver,” said senior study author Scott L. Friedman, MD, the Irene and Arthur M. Fishberg professor of medicine, dean for therapeutic discovery, and chief of liver diseases at Icahn Mount Sinai. “In combining this new glass liver imaging approach—an advanced tissue clearing method that enables deep insight—along with gene expression analysis in individual stellate cells, we have unveiled an entirely new understanding of how these cells generate scarring as NASH advances to late stages.”
“We confirmed the importance of one such pair of proteins, NTF3-NTRK3, using a molecule already developed to block NTRK3 in human cancers and repurposed it to establish its potential as a new drug to fight NASH fibrosis,” said first author Shuang (Sammi) Wang, PhD, an instructor in the division of liver diseases. “This new understanding of fibrosis development suggests that advanced fibrosis may have a unique repertoire of signals that accelerate scarring, which represent a previously unrecognized set of drug targets.”
The researchers are currently working with Icahn Mount Sinai chemists to further optimize NTRK3 inhibitors for the treatment of liver fibrosis. They hope to extend their efforts to determine if similar interactions among fibrogenic cells underlie fibrosis of other tissues including the heart, lung, and kidneys.
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.”
A study of more than 1,300 women demonstrated that HIV is an independent risk factor for nonalcoholic steatohepatitis with significant nonalcoholic fatty liver disease activity and fibrosis, researchers reported.
“Nonalcoholic fatty liver disease (NAFLD) is common among people with and without HIV and is a leading cause of liver-related morbidity and mortality,” Jennifer C. Price, MD, PhD, associate professor of medicine at the University of California, San Francisco, told Healio. “However, most patients with NAFLD do not go on to develop cirrhosis.”
Women living with HIV faced a higher risk for nonalcoholic steatohepatitis with significant nonalcoholic fatty liver disease activity and fibrosis.
According to Price, the FibroScan-AST (FAST) score can identify patients at risk for developing cirrhosis, or those with nonalcoholic steatohepatitis with an elevated NAFLD activity score and significant liver fibrosis.
“The advantage of the FAST score is that it does not require liver biopsy,” Price said. “We conducted this study to see if HIV was independently associated with higher risk of an elevated FAST score in a cohort of women with and without HIV.”
Jennifer C. Price
Price and colleagues assessed 1,309 women without history of chronic viral hepatitis at 10 U.S. sites 928 with HIV and 381 who were HIV negative — and evaluated associations between HIV, demographic, lifestyle and metabolic factors with a FAST score higher than 0.35, which is considered elevated.
Women with HIV were more likely to have an elevated FAST score compared with those without HIV (6.3% vs 1.8%; P = .001). The researchers calculated that HIV infection was associated with 3.7-fold higher odds of elevated FAST score (P = .002), whereas a greater waist circumference was associated with 1.7-fold higher odds per each 10 cm (P <.001).
The study also showed that undetectable HIV RNA and current protease inhibitor use were independently associated with lower odds of elevated FAST score.
“HIV may increase the risk of more advanced NAFLD histology and liver disease progression,” Price said. “Unsuppressed HIV viral load and increased waist circumference are risk factors for elevated FAST in women, underscoring the importance of ART adherence and weight management in clinical practice.”
This link wasn’t fully explained by obesity, insulin resistance, researchers say
Abnormal periods may put young women at a higher risk for developing nonalcoholic fatty liver disease (NAFLD), a Korean study suggested.
Among 72,092 premenopausal women under the age of 40, long or irregular menstrual cycles were linked to a 22% higher risk for incident NAFLD after adjusting for age, BMI, insulin resistance, and other factors (HR 1.22, 95% CI 1.14-1.31), reported Seungho Ryu, MD, PhD, of Sungkyunkwan University School of Medicine in Seoul, and colleagues.
More specifically, women with irregular cycles lasting over 31 days in between periods saw this increased risk, with 40-day or longer cycles tied to the highest risk:
31- to 39-day cycles: HR 1.27 (95% CI 1.15-1.39)
≥40-day cycles: HR 1.49 (95% CI 1.38-1.60)
“Importantly, our results indicate that menstrual irregularity, which is easier to diagnose and usually presents earlier than PCOS [polycystic ovary syndrome], highlights the possibility of identifying premenopausal women at risk of developing NAFLD,” Ryu’s group wrote.
“This link was not explained by obesity,” Ryu added in a statement. “Previous studies have shown that long or irregular menstrual cycles are associated with type 2 diabetes and cardiovascular disease, but our study is the first to find a link between long or irregular menstrual cycles and NAFLD.”
“Young women with long or irregular menstrual cycles may benefit from lifestyle changes to reduce the risk of NAFLD as well as other cardiometabolic diseases,” he suggested.
In a subgroup analysis of women with a homeostatic model assessment of insulin resistance (HOMA-IR) less than 2.5 — indicating less insulin resistance — these associations were weakened but were still significantly high: women with 31- to 39-day and ≥40-day irregular menstrual cycles saw an 18% and 27% higher risk for developing NAFLD, respectively.
“This suggests that insulin resistance, which has been posited to contribute to the association between PCOS and NAFLD, does not fully explain the association between long or irregular menstrual cycles and NAFLD demonstrated in our study,” the researchers pointed out.
The group explained that while the mechanisms underlying the association between long or irregular menstrual cycles and NAFLD aren’t fully clear just yet, some possible explanations could be estrogen exposure, androgen excess, and hypogonadotropic hypogonadism.
The study’s final cohort included Korean women under the age of 40 who underwent annual exams at a health center in Seoul and Suwon, South Korea. Exclusion criteria included a history of liver disease, hepatitis B or C, higher alcohol consumption, and abnormal thyroid functioning.
NAFLD diagnosis was based on hepatic steatosis identified on abdominal ultrasonography performed by radiologists. At baseline, 7.1% of women had prevalent NAFLD and 27.7% had long or irregular menstrual cycles. During a median 4.4-year follow-up period, 8.9% of women developed incident NAFLD.
Ryu’s group noted that diagnosing NAFLD via ultrasonography instead of histological diagnosis — the “gold standard” — was a limitation to the study, but explained that ultrasonography was a more appropriate option for routine health screening examinations.
Obesity and weight gain are independently associated with an increased risk for fibrosis progression in patients with nonalcoholic fatty liver disease (NAFLD), a large cohort study has found. Weight loss was negatively associated with fibrosis progression.
“This association remained significant after adjustment for confounders including baseline BMI [body mass index], indicating that weight change per se is an independent risk factor for fibrosis progression. Higher BMI at baseline was also positively associated with APRI [aspartate aminotransferase to platelet ratio index] progression,” the researchers write.
The study, by Yejin Kim, MHS, Center for Cohort Studies, Total Healthcare Center, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, South Korea, and colleagues, was published online July 15 in Clinical Gastroenterology and Hepatology.
The researchers analyzed data from 40,700 adults who received comprehensive annual or biennial examinations as part of the Kangbuk Samsung Health Study. They included participants with fatty liver, as evidenced on abdominal ultrasonography, who had undergone a health examination between 2002 and 2016 and who had had two or more follow-up visits through the end of 2016. Patients were followed for a median of 6 years.
The authors explain that they used APRI score to assess fibrosis progression because it is noninvasive and the formula includes neither BMI nor age. The study’s primary endpoint was the development of intermediate to high probability of advanced fibrosis, as assessed by APRI.
The researchers first adjusted for age and sex, and later adjusted for center, year of screening examination, smoking status, alcohol consumption, regular exercise, education level, BMI, diabetes history, cardiovascular disease history, and hypertension history. A second model also adjusted for homeostatic model assessment of insulin resistance (HOMA-IR) and high-sensitivity C-reactive protein (hsCRP).
There were 275,421.5 person-years of follow-up, during which 5454 patients with low APRI progressed to intermediate or high APRI.
When stratified into quintiles by weight change, those with the greatest weight loss (-43.4 to -2.3 kg) had a significantly reduced risk for progression (hazard ratio [HR], 0.68; 95% confidence interval [CI], 0.62 – 0.74), compared with those whose weight was stable. Similarly, patients with small degrees of weight loss (-2.2 to -0.6 kg) had a reduced risk for progression (HR, 0.86; 95% CI, 0.78 – 0.94).
By contrast, any weight gain appeared to increase progression risk. Specifically, those who gained a smaller amount of weight (0.7 to 2.1 kg) showed a 17% risk increase (HR, 1.17; 95% CI, 1.07 – 1.28), and those who gained more (2.2 to 26.5 kg) had a 71% increased risk (HR, 1.71; 95% CI, 1.58 – 1.85).
These associations were not mediated by inflammation or insulin resistance after adjustment for HOMA-IR and hsCRP.
Compared with those whose baseline BMI was from 18.5 to 22.9 kg/m2, the HRs for APRI progression were as follows: 1.67 (95% CI, 0.74 – 3.73) for BMI of <18.5 kg/m2; 1.13 (95% CI, 1.02 – 1.26) for BMI of 23 – 24.9 kg/m2; 1.41 (95% CI, 1.28 – 1.55) for BMI of 25 – 29.9 kg/m2; and 2.09 (95% CI, 1.86 – 2.36) for BMI of ≥ 30. All values were determined after adjusting for age, sex, health center, year of screening examination, smoking status, alcohol consumption, exercise, education, diabetes history, cardiovascular disease history, and hypertension history. These associations remained significant after adjustments for HOMA-IR and hsCRP.
“When the impact of weight change on APRI worsening was compared with that of other metabolic factors, increasing quintiles of weight change, triglyceride, uric acid, and HOMA-IR and decreasing quintiles of high-density lipoprotein cholesterol were associated with increased risk of APRI worsening in a dose-response manner (all P for trend <.001), with weight change showing the greatest magnitude of association among the metabolic factors evaluated,” the authors explain.
The associations of both weight change and BMI with APRI progression were still seen in patients with NAFLD who had no history of diabetes or cardiovascular disease.
“Although the mechanisms underlying the association between excessive adiposity or fat gain and the fibrosis progression are not yet fully understood, insulin resistance and inflammation are thought to be involved,” the researchers write. “However, after adjustment for HOMA-IR and hsCRP, the association between obesity, weight gain, and fibrosis progression remained significant. Multiple other factors, including oxidative stress and lipotoxicity, have also been implicated in fibrosis progression.”
Study limitations include the use of ultrasonography to diagnose NAFLD. Although liver biopsy is considered the gold standard, it is not be feasible in a large, low-risk population, and abdominal ultrasound is acceptable, the authors say. Also, although APRI “has demonstrated a reasonable utility as a noninvasive method for the prediction of histologically confirmed advanced fibrosis…there are no currently available longitudinal data to support the use of worsening noninvasive fibrosis markers as an indicator of histologic progression of fibrosis stage over time.”
The study was conducted among fairly healthy young and middle-aged Koreans and may not be generalizable to those of other ages, or to groups in which comorbidities are more prevalent, or to other racial or ethnic groups.
“In this large cohort study of young and middle-aged adults with NAFLD, obesity and weight gain were significantly and independently associated with an increased risk of developing fibrosis progression. Strategies for maintaining a healthy weight and preventing weight gain may help reduce fibrosis progression and its associated consequences in individuals with NAFLD,” the researchers conclude.
Quantitative chemical shift-encoded magnetic resonance imaging (CSE-MRI) is an effective, noninvasive way to monitor liver fat levels over time after bariatric surgery, a study published today in Radiology reports.
Common in obese people, nonalcoholic fatty liver disease (NAFLD) can progress to fibrosis, cirrhosis, and cancer. Although weight loss can reduce the extent of NAFLD, biopsy has been the only possible method of assessing the long-term impact of weight loss on hepatic steatosis.
B. Dustin Pooler, MD, an adjunct assistant professor at the University of Wisconsin School of Medicine and Public Health and a radiologist at Madison Radiologists, S.C., in Madison, Wisconsin, and colleagues used the noninvasive MRI technique to measure average liver proton density fat fraction (PDFF) in 50 patients before bariatric surgery and at several points during the year afterward. They compared this MRI biomarker with postsurgical changes in body mass index (BMI), weight, and waist circumference.
The study cohort, which included 43 women and seven men and was recruited from 2010 to 2015 from medical centers at the University of California San Diego and the University of Wisconsin-Madison, had a mean age of 51.0 years and a mean BMI of 44.9 kg/m2.
Presurgical preparation entailed a very low-calorie diet of 600 to 900 calories per day, started at a mean of 2.6 weeks before surgery. Bariatric procedures included gastric banding (n = 2), gastric bypass (n = 28), gastric sleeve (n = 19), and gastric plication (n = 1). PDFF was assessed presurgically before and after the diet, and along with anthropomorphic measurements was assessed at 1, 3, and 6 months after surgery.
Liver fat content began to normalize early during the low-calorie diet and soon after surgery, suggesting metabolic disturbances of NAFLD begin to correct rapidly in response to the caloric deficit of the presurgical diet even before substantial weight loss.
Overall, 32 (64%) of 50 study participants saw their liver fat normalized and an estimated 90% reached that goal by 42 weeks. Six to 10 months postsurgery, patients’ mean PDFF had returned to the normal range of < 5%, falling from 18.1% to 4.9%, with a mean estimated time to normalization of 22.5 weeks.
Mean BMI fell to 34.5 kg/m2 (mean decrease 10.4), and the cohort’s final mean weight of 91.6 kg represented am overall reduction of 29.9 kg. The final mean waist circumference of 110.9 cm represented a mean decrease of 21.3 cm. All reductions were statistically significant (P < .0001)
Rohit Loomba, MD, director of the NAFLD Research Center at the University of California San Diego and chair of the NAFLD Special Interest Group for the American Association for the Study of Liver Diseases, told Medscape Medical News the findings are an important contribution to the field of liver study.
“Previously the MOZART trial conducted by our group demonstrated the role of MRI-PDFF in assessing treatment response in [nonalcoholic steatohepatitis; NASH] trials. This excellent study clearly extends those findings to examine longitudinal changes in liver fat by MRI-PDFF specifically after bariatric surgery,” said Loomba, who was not involved in the research.
Loomba noted that further studies are needed to examine longitudinal changes that might suggest progressive NAFLD, including biomarkers of fibrosis and inflammation.
Earlier this year, Duke University researchers confirmed MRI’s utility for detecting NAFLD, but concluded it was not sufficiently accurate to replace biopsy in distinguishing between NAFLD and its more advanced relative, nonalcoholic steatohepatitis.
Interestingly, whereas initial PDFF level strongly predicted both rate of liver fat change and time to normalization, body anthropometrics did not predict either outcome. “Decreases in liver fat content were only weakly correlated with starting weight and the amount of overall weight loss, suggesting possible utility in monitoring liver fat with MRI following bariatric surgery, independent of monitoring weight loss,” Pooler and colleagues write.
They suggest that PDFF measurements could also help identify appropriate candidates for bariatric surgery as a result of this robust association between liver fat reduction and pretreatment steatosis levels.
According to the authors, their study is the first longitudinal analysis of changes in liver fat over time in a bariatric surgery population.
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