fatty liver disease

American Association of Clinical Endocrinology Clinical Practice Guideline for the Diagnosis and Management of Nonalcoholic Fatty Liver Disease in Primary Care and Endocrinology Clinical Settings

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Abstract

Objective

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.

Fatty liver disease conditions ‘change the healthy heart to a failing heart’

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CVD risk increases with the severity of nonalcoholic fatty liver disease, and both CV and liver events are “highly related” to the degree of hepatic fibrosis present, according to a speaker.

CVD remains the leading cause of death in adults with nonalcoholic steatohepatitis (NASH) and liver fibrosis, Bart Staels, PhD, professor at the Faculty of Pharmacy, University of Lille, France, said during a presentation at the World Congress on Insulin Resistance, Diabetes & Cardiovascular Disease. Data also show adults with biopsy-proven NAFLD have increased incidence of major adverse cardiac events, caused by atherosclerosis as well as valvular calcification and myocardial remodeling.

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CVD risk climbs as the severity of nonalcoholic fatty liver disease increases, and CVD remains a leading cause of death for people with nonalcoholic steatohepatitis and liver fibrosis. Source: Adobe Stock

“Patients with NASH are at elevated risk to develop CVD, but when the disease progresses — and especially when fibrosis kicks in — the risk goes much higher,” Staels said. “It is important when we discuss a link between NAFLD and the heart that we split NAFLD/NASH as one group, and [people with] fibrosis as another group.”

Connections between liver, heart

Many mechanisms could explain how the pathology of fatty liver disease has such an impact on CVD, Staels said during the presentation. People with NAFLD are often obese and have type 2 diabetes, comorbidities that further increase CV risk.

“It is no surprise that in the presence of insulin resistance and type 2 diabetes, these patients are at higher CV risk,” Staels said. “The liver plays an important role in this part of the mechanism, because hepatic insulin resistance is important with respect to the development of fatty liver, steatosis and type 2 diabetes.”

The liver also plays a role in progression of atherogenic dyslipidemia, Staels said. In the settings of insulin resistance, metabolic syndrome and type 2 diabetes, dyslipidemia is characterized by high production of VLDL particles and low HDL, further contributing to increased CV risk, Staels said.

Role of genetics

Several genes are believed to play a role in NASH and NAFLD; however, all genes linked with development of fatty liver also play a role in lipid metabolism, Staels said.

“Depending on your genetic constellation … you can have less VLDL production, meaning the lipids stay in the liver, but when you have a different [genetic] isoform, it enhances hepatic VLDL production, promoting atherosclerosis,” Staels said. “The link between the liver, lipid production and the risk it confers to the heart can be quite complicated if one tries to interpret it by identifying how genetic variants contribute.”

Emerging research also suggests apolipoprotein F (ApoF), a liver-secreted protein present on HDL and LDL particles, reduces plasma triglycerides through enhanced remnant clearance by the liver.

“We think the downregulation of ApoF in NAFLD is somehow a protection mechanism, to protect the liver from cholesterol overload, but that this happens at the expense of atherogenic dyslipidemia and possibly CVD risk,” Staels said. “We are working on this connection. This link between lipid metabolism in the liver and CV risk may also be quite complicated.”

Targeting inflammation

As in other metabolic conditions, chronic inflammation is also present in NAFLD and NASH, Staels said. Immune phenotyping in people with diagnosed NASH shows lower levels of regulatory anti-inflammatory T cells; new research aims to target immune cells as a potential NASH treatment, Staels said.

“What becomes quite clear is the metabolic components of these diseases also touch the immune cells,” Staels said. “This is due to the fact that they are also overloaded with fatty acid, inducing an inflammatory response.”

The liver-induced immune response also affects cardiac remodeling, Staels said.

In a cohort of patients who underwent catheter ablation for atrial fibrillation, Staels and colleagues observed patients presenting with metabolic associated fatty liver disease at risk for liver fibrosis exhibited increased left atrial remodeling with impaired hemodynamic, electrophysiological and histopathological properties, including altered myeloid cells and an altered immune profile.

“There really is a connection, tied to alterations in circulating immune cells,” Staels said. “We think conditions of NAFLD, NASH pathogenesis can change the healthy heart into a potentially failing heart and that immune cells and interaction with cardiac myocytes and fibroblasts play an important role.”

Liver fibrosis may drive AF

CV and liver events are highly related to the degree of liver fibrosis and liver fibrosis is likely associated with occurrence of AF, Staels said. Data also show higher liver fibrosis scores are associated with adverse atrial remodeling and AF recurrence after catheter ablation.

“This is quite an interesting observation that links NAFLD and fibrosis not only to the classical atherosclerotic model, but directly to cardiac muscle,” Staels said. “This may spawn more research to go further in that direction,” Staels said.

As Healio previously reported, eight professional societies issued a joint report on the dangers associated with NAFLD and NASH in 2021, calling on clinicians to work together across specialties and align treatment strategies.

Perspective

Scott Isaacs, MD, FACE, FACP)

Scott D. Isaacs, MD, FACE, FACP

The global prevalence of NAFLD has risen substantially, together with the obesity pandemic affecting one in three middle-aged adults in the U.S. NAFLD is considered the hepatic manifestation of the metabolic syndrome and is closely linked to visceral adiposity, insulin resistance, chronic inflammation and lipotoxicity.

Type 2 diabetes and NAFLD have a reciprocally injurious relationship mediated through common pathophysiology magnifying the risk for CV events. NAFLD is associated with hypertension and an especially atherogenic dyslipidemia with high VLDL, hypertriglyceridemia, small dense LDL particles and low HDL. As such, the leading cause of death in patients with NAFLD is CVD, not liver disease. The increased risk of both fatal and nonfatal CV events has been correlated with the severity of hepatic steatosis, inflammation, or fibrosis.

The FIB-4 score predicts CV risk, where those with FIB-4 score greater than 2.67 have a 4-fold increased risk of having a CV event compared with those with a FIB-4 score < 2.67. There is a correlation with NAFLD and atrial fibrillation and ventricular arrhythmias as well as other cardiac complications, such as heart failure with preserved ejection fraction, cardiomyopathy, and cardiac valvular calcification. However, it is difficult to establish a causal relationship between NAFLD and CVD, given the entanglement of overlapping metabolic disturbances in these individuals.

Scott D. Isaacs, MD, FACE, FACP

Adjunct Associate Professor of Medicine

Emory University School of Medicine

Source: http://www.healio.com

Is ‘Juliet’ Unwittingly Poisoned in Today’s Environment?

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Examining the dangers of Is ‘Juliet’ Unwittingly Poisoned in Today’s Environment?

Two rubber stamps with the words paraben, bisphenol A & phthalate printed on paper background. Endocrine disruptors concept.

What could connect such disquieting and disparate health concerns as early onset puberty, female depression, and fatty liver disease? Endocrine disrupting chemicals (EDCs) are leading candidates for all of these health aberrations. Moreover, these chemicals have become ubiquitous in the contemporary U.S. environment as well as globally. Virtually all humans born today are exposed to a variety of chemicals, especially EDCs that are measurably detectable in common products and in most humans.

Despite the health risks, these chemicals have not received enough public attention. This warrants greater action from the medical and scientific community to ensure policymakers are informed.

The Impact of EDCs on Certain Disease States

Early Onset Puberty

Studies show that the age of pubertal onset has declined continuously for 3 decades, and evidence suggests EDCs may play a role. More specifically, this may be related to the multitude of EDCs that include bisphenol A (BPA), polyfluoroalkyl substances (PFAS), and polybrominated diphenyl ethers (PBDE). Experimental research suggests a causative role for these chemicals: in particular, EDCs are actively disrupting function at several levels of the hypothalamic-pituitary-gonadal axis as well on peripheral tissues. EDCs disrupt the gonadotropin-releasing hormone (GnRH) pulsatile release and also alter several epigenetic mechanisms that may have transgenerational effects.

One area warranting further study is whether EDCs are synergistic with one another. However, there is already substantial evidence that this is the case, and that certain interactions can effect neurodevelopment. For example, one complex study found increased risk of language delay among the offspring of more than half of the pregnant women in the study who had been exposed to an EDC mixture — a remarkably high prevalence.

Hormone Signaling and Depression

Research suggests that EDCs interfere with hormone signaling and increase human vulnerability to neuropsychiatric disorders. Moreover, evidence is accumulating that they impair serotonergic neurotransmission, thus contributing to the development of depression and its concomitants. There is mounting evidence that these chemicals are associated with increased risk of depression in the peripartum period of mothers, while other studies suggest early exposure to EDCs including in breast milk may contribute to depression later in childhood and adolescence.

Fatty Liver Disease

EDCs have also been implicated in a range of physical disorders increasing in the 21st century, including fatty liver disease and diabetes mellitus. Fatty liver disease includes non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH), which can progress to cirrhosis (end stage liver disease) or even the highly lethal hepatocellular cancer. Of note, the U.S. is not alone in this epidemic. Recent research suggests nearly one-third of adults worldwide have NAFLD, with a U.S. prevalence perhaps as high as 38% of the adult population.

EDCs acting in concert with a high fat diet and high fructose and sucrose intake may further contribute to fatty liver disease and early EDC exposure may be crucial. Adolescents with NAFLD have an increased chance of developing depression at ages 15-17 compared to those without it. Moreover, investigators in another study observed 11.6% of female adolescents with NAFLD had suicidal tendencies. In the past decade, NAFLD and its sequelae have become the leading cause of liver transplantation in women in the U.S. This costly and difficult procedure does not guarantee a normal life expectancy, although it is highly effective at preventing immediate death from hepatic failure.

Spermatogenesis and Romeo Too

So far we have focused exclusively on the impact of these ubiquitous toxic chemicals on women, suggesting “Juliet” may be getting poisoned without realizing it. But “Romeo” is not spared either. EDCs have been shown to impair spermatogenesis, and may contribute to reduced male fertility. With the birthrate in the U.S. falling for the sixth consecutive year (echoing global trends), it’s worth exploring further whether these may be inter-related phenomena.

COVID-19

Growing evidence suggests EDCs may be linked to more severe COVID-19 outcomes because they can localize to lung tissue, contribute to immune dysregulation, and promote neuroinflammation.

There are other health risks of EDCs that we haven’t mentioned in this brief essay.

Informing Policymakers and the Public

Of course, not all chemicals have the same effects on various disease states and severity: some are more toxic than others and have different health outcomes. But these chemicals are highly prevalent — they are found in a wide range of foods, water, personal products, and packaging. In addition to phthalates, BPA, and PFAS, other environmental toxins including air pollution, pesticides, and herbicides may be adding to this burden of toxicant related disorders.

Shouldn’t this raise serious questions among physicians, scientists, and policymakers to ensure the public is better informed of the health risks? Given the dangers of these chemicals it is indeed surprising that the public is not better informed. However, first it is up to the medical and scientific community to inform policymakers of the risks involved. But medical scientists and practitioners alike tend to be narrowly focused on the issues concerning to their specific disciplines while avoiding engagement with broader issues of health and disease. This has led to lack of knowledge about population health risks of environmental toxicants among other complex issues. More attention should be given to the insights of professors of environmental health who are often found in schools of public health.

While the Biden administration made a recent move to label certain “forever chemical” as hazardous, more needs to be done. Without a better-informed public and policymakers, efforts to mitigate the risks of chemical toxicity and develop sound public policy won’t go far enough. It’s essential we limit the manufacture and/or distribution of such damaging chemicals, and increase clinical research on how to minimize the adverse health effects of these unfortunately ubiquitous substances.

The future of humans is fraught chemically as well as climatologically. Can’t the medical scientific community lead more effectively on this health matter of imminent peril?

Increased fatty liver disease awareness needed to mitigate burden among young adults

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Increased awareness is needed to mitigate burden fatty liver disease and modifiable risk factors among adolescents and young adults, according to research presented at The Liver Meeting Digital Experience.

“The prevalence of fatty liver disease is potentially increasing in adolescents and young adults, what we call the AYA population, and this is due to increased rates of alcohol consumption in recent years leading to an increase in alcohol-associated fatty liver disease, or ALD, and the obesity pandemic leading to an increase in the prevalence of nonalcoholic fatty liver disease, or NAFLD,” Naim Alkhouri, MD, vice president of academic affairs and director of the Fatty Liver Program at Arizona Liver Health, said. “Previous studies that estimated the prevalence of fatty liver disease in the AYA population relied on liver enzymes or liver ultrasound with known issues in terms of sensitivity and specificity.”

Among adolescents and young adults who consumed alcohol excessively, suspected fatty liver was present in: Alcohol-associated fatty liver disease: 42.4%; Nonalcoholic fatty liver disease: 39%

To assess the prevalence and burden of alcohol-associated fatty liver disease (ALD) and nonalcoholic fatty liver disease, researchers analyzed data from the National Health and Nutrition Examination Survey database for adolescents and young adults aged 15 years to 39 years with valid FibroScan measurements. They further divided the study population by excessive alcohol consumption (males: > 2 drinks/day; females: > 1 drink/day) and generated controlled attenuation parameter scores ([CAP] 248 dB/m) to identify subjects with suspected ALD and NAFLD.

According to study results, subjects who consumed alcohol excessively were older (28.1 years vs. 26.2 years), had a higher BMI (29.2 kg/m2 vs. 27.6 kg/m2), were current smokers (51% vs. 17.9%) and were more likely to be male (63.4% vs. 51.1%).

Suspected ALD was present in 42.4% of subjects (95% CI, 36.5-48.4) with suspected significant and advanced fibrosis present in 17.7% (95% CI, 13-23.6) and 9.4% (95% CI, 6.5-12.3), respectively. Among subjects without excessive alcohol consumption, 39% (95% CI, 35.6-42.4) had suspected NAFLD with suspected significant and advanced fibrosis present in 25.1% (95% CI, 21.3-29.5) and 14.4% (95% CI, 9.7-20).

“A significant percentage of adolescents and young adults in the United States are at risk for alcohol associated liver disease and nonalcoholic fatty liver disease and a subset of these subjects are at risk of significant liver fibrosis and even advanced liver fibrosis,” Alkhouri concluded. “Therefore, efforts should focus on increasing awareness of the burden of ALD and NAFLD in this population and to mitigate modifiable risk factors to prevent disease development and disease progression to potentially advanced fibrosis and cirrhosis.”

Multiple Drugs Advance for Fatty Liver Disease

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Although numerous drugs for nonalcoholic steatohepatitis (NASH) have shown positive results in phase 2 clinical trials, the cure might lie in combinations of drugs with different mechanisms, experts say.

In fact, curing NASH might turn out to be as challenging as curing type 2 diabetes, said Sidney Barritt IV, MD, from the University of North Carolina at Chapel Hill.

Unlike hepatitis C, which can be treated with the blockbuster antiviral drugs that have recently proven so effective, NASH is more complicated because there are no effective drugs to treat it.

With the obesity epidemic, NASH is increasingly common, and results from phase 2 trials attracted throngs of conference-goers with questions here at The Liver Meeting 2018.

Some of the results look encouraging, Barritt told Medscape Medical News. “I think they’re clinically significant.”

Phase 2 results have been positive for MGL-3196 (Madrigal Pharmaceuticals), GS-9674 (Gilead Sciences), NGM282 (NGM Bio), arachidyl amido cholanoic acid (Aramchol, Galmed Pharmaceuticals), tropifexor (Novartis), and VK2809 (Viking Therapeutics).

All the drugs reduced liver fat measured with MRI-derived proton density fat fraction (PDFF). The drugs also improved various other measures of the disease, such as NASH Activity Score, fibrosis, and alanine aminotransferase.

These NASH agents add to the four already in phase 3 trials: obeticholic acid (Ocaliva, Intercept Pharmaceuticals), elafibranor (Genfit), selonsertib (Gilead), and cenicriviroc (Tobira Therapeutics).

But no clear winner has emerged from these studies. It’s hard to know how well the biomarkers measured in trials will protect patients from sickness and death, Barritt explained. NASH destroys the liver gradually; most of its victims die from the heart disease or cancer that results from this damage, which takes decades.

The real test is going to be real-world efficacy. Are the drugs going to have the impact that we expect them to have based on the clinical trial data?

“The real test is going to be real-world efficacy,” he said. “Are the drugs going to have the impact that we expect them to have based on the clinical trial data?”

The development of NASH is mostly related to lifestyle factors, such as overeating and lack of exercise, so there is no obvious target for a drug as there is with a virus. As a result, drug makers have focused on various aspects of inflammation, fat accumulation, and scar formation.

Like obeticholic acid, GS-9674 and tropifexor are farnesoid X receptor (FXR) agonists, which help regulate bile acids, carbohydrate and lipid metabolism, and insulin sensitivity. They also play a role in growth and regeneration after liver injury.

MGL-3196 and VK2809 are thyroid hormone-receptor beta agonists designed to mediate the effects of the thyroid hormone on the liver, on low-density-lipoprotein cholesterol, on triglycerides, on fatty liver, and on insulin sensitivity.

Arachidyl amido cholanoic acid inhibits stearoyl CoA desaturase. It has a “dual mode of action on liver fibrosis, downregulation of steatosis, and a direct effect on hepatic stellate cells, the human collagen-producing cells,” according to Galmed Pharmaceuticals.

The potential for all these approaches was evident in the phase 2 results presented. But the most effective treatments might be a combination of drugs that act on different pathways, said Keyur Patel, BM, from Duke University in Durham, North Carolina, who is a GS-9674 investigator.

In a separate phase 2 trial now underway, Gilead is testing the combination of GS-9674 plus selonsertib, a small-molecule inhibitor of apoptosis signal-regulating kinase 1 (ASK1), plus GS-9676, an acetyl-CoA carboxylase inhibitor, Patel told Medscape Medical News.

A Strong Placebo Effect

Combining the drugs makes sense because the drugs now in phase 3 trials have not shown the potential to cure NASH on their own, according to Jerry Colca, PhD, chief scientific officer of Cirius Therapeutics in Kalamazoo, Michigan. “They have shown minimal effects in phase 2b,” he said.

One of the challenges that researchers have is the strong placebo effect, Colca told Medscape Medical News. Patients in placebo groups typically diet and exercise, which addresses the underlying cause of NASH, and drugs don’t always show much improvement over that.

Cirius is currently conducting a phase 2b study of MSDC-0602K, an insulin sensitizer “designed to selectively modulate the mitochondrial pyruvate carrier (MPC), which at the cellular level mediates the effects of overnutrition,” the company reports.

The effect of MSDC-0602K on NASH might be broader than that of competing drugs because it acts further upstream, Colca noted.

In the phase 2 studies presented, the drugs appear to be well tolerated, although some adverse events, such as pruritus and diarrhea, were reported.

Many of the questions about these drugs might not be addressed until they are already on the market.

“What we don’t know from these trials is what the expected duration of therapy will be,” Barritt said. “Are they drugs for 1 to 3 years to reset the clock while the patient addresses diet and exercise? Or are they going to be lifetime medications?”

Different Sugars, Different Risks

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Study shows fructose more damaging than glucose in fatty liver disease

If you’re one of the 2 billion people in the world who are overweight or obese, or the 1 billion people with fatty liver disease, your doctor’s first advice is to cut calories—especially cutting down on concentrated sugars such as high-fructose corn syrup, a sugar found in sweetened beverages and many other processed foods.

Harvard Medical School researchers at Joslin Diabetes Center have found that mice on a fatty diet who were given high levels of fructose in their diet suffered much worse metabolic effects than those given similar amounts of calories as glucose (another component of table sugar). The scientists went on to pinpoint biological processes that help explain the different outcomes.

Although fatty liver disease usually does not progress to dangerous levels of liver inflammation, the condition is an increasing concern as its rates climb in the worldwide obesity epidemic, said Samir Softic, first author on a paper in the Journal of Clinical Investigation describing the research.

Additionally, the condition has become a particular concern in children, said Softic, who is also an HMS instructor in pediatrics at Boston Children’s Hospital and a researcher in the lab of C. Ronald Kahn.

Researchers experimented in a mouse model used to study obesity, type 2 diabetes, fatty liver and other metabolic illnesses. These animals were given either regular or high-fat diets and drank either plain water or water sweetened with fructose or glucose.

Comparing these six diets, “gave us a much more precise way of saying what is the role of fructose versus glucose in the diet, and how bad is it when it’s added to a normal diet versus a diet high in fat,” said Kahn.

Over 10 weeks, none of the animals on a regular diet developed insulin resistance, a key factor in metabolic disease, although those consuming either form of sugar gained substantially more weight.

Among animals on the high-fat diet, however, significant differences emerged between the fructose and the glucose groups.

“Fructose was associated with worse metabolic outcomes,” said Softic.

Mice on the high-fat diet became much more obese and more insulin-resistant compared to their peers on the glucose diet. And while both groups of animals added fat to their livers, the fat composition was quite different.

The researchers also discovered that production of an enzyme called Khk (ketohexokinase), required for the first step of fructose metabolism, was increased in the livers of mice that drank fructose. When the scientists examined liver samples from obese human teenagers with fatty liver disease, they also found higher levels of Khk.

The Khk enzyme is specifically important in fructose, but not glucose, metabolism. “Although fructose and glucose are both sugars, cells handle them very differently,” said Kahn.

The scientists saw that this might offer a target to clamp down on fructose metabolism.

To follow up on this possibility, the team collaborated with researchers at Alnylam Pharmaceuticals in Cambridge, Mass., to tamp down on production of the Khk protein in the liver. The treatment lowered liver weight and improved glucose tolerance among mice on any diet, but most strikingly among those on the high-fat/high-fructose diet.

Looking ahead, the researchers will continue to explore the Khk biological pathway and to look for other promising molecular targets for treating fatty liver disease.

“This disease is almost always associated with obesity,” noted Kahn. “Once your fat cells get really full of fat, and they can’t hold any more, fat winds up going in other tissues, and the liver is the next best place.”

Almost all obese people with diabetes add some fat to their livers.

“These people are more at risk of developing fatty liver disease, just as those with fatty liver disease are more at risk of developing diabetes, since obesity is a predisposing factor for both conditions,” said Softic.

As obesity spreads worldwide, so will the burden of fatty liver disease and associated liver failure, which is predicted to become the most common factor driving the need for liver transplants, he said.

The disease afflicts people of every age, but has become a particular problem in children, now that about one-fifth of U.S. school-age children are obese, according to the Centers for Disease Control and Prevention.

“The disease is much more worrisome in a child of 13 who goes from normal liver to fatty liver to liver inflammation over the span of several years than in somebody who’s been overweight for 30 years,” says Softic. “Kids also eat more sugar than adults, so fructose may be even more of a risk factor in children, which would add to their years of poor health.”

Links Between Fatty Liver Disease and Polycystic Ovary Syndrome

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The possible link between these two conditions may have a number of implications for the diagnosis and treatment of various diseases among women.

A growing body of research indicates that non-alcoholic fatty liver disease (NAFLD) and polycystic ovary syndrome (PCOS) may be related and, due to shared mechanisms, may increase the risk of type 2 diabetes (T2D) and other cardiometabolic complications. The findings may have a number of implications for the diagnosis and treatment of various diseases.

Although the etiology of PCOS, one of the most common endocrine disorders in women of reproductive age, is uncertain, obesity and insulin resistance are frequently present in affected individuals, and they play a role in its development. The condition affects 5% to 18% of this population depending on the diagnostic criteria used, and clinical features consist of menstrual dysfunction, infertility, hirsutism, acne, and alopecia.

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Similarly, obesity and insulin resistance appear to contribute to the pathogenesis of NAFLD, which is characterized by increased accumulation of fat in the liver in the absence of significant alcohol consumption. NAFLD includes a range of diseases, from simple steatosis to non-alcoholic steatohepatitis to cirrhosis, and it has an estimated worldwide prevalence of 6.3% to 33.0%; however, if obesity or T2D is involved, the prevalence of NAFLD rises to approximately 75%.

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A connection, but few reasons as to why

NAFLD and PCOS occur together more frequently than expected, in many cases simply by chance alone. Studies have consistently shown that NAFLD rates are elevated in young women with PCOS, independent of weight and metabolic syndrome features, and limited data suggest that these women have better odds of experiencing more severe forms of NAFLD.

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In one recent study, by Evangeline Vassilatou, MD, PhD, an endocrinologist at the Attikon University General Hospital, in Athens, Greece, NAFLD was detected in 71 of 110 (64.5%) overweight and obese (yet otherwise apparently healthy) premenopausal women, and women with NAFLD were more often diagnosed with PCOS than women without NAFLD (43.7% versus 23.1%, respectively).

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It’s currently unclear how the two conditions may influence each other: Are they a consequence of shared risk factors? Or does one condition contribute to the other independently of these factors? Accumulating evidence indicates that NAFLD may exacerbate insulin resistance and release multiple pro-inflammatory, pro-coagulant, and pro-fibrogenic mediators that could contribute to the pathophysiology of PCOS.

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On the other hand, insulin resistance and androgen excess are the main characteristics of PCOS that could increase the risk of developing NAFLD.

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To examine the most relevant factors associated with NAFLD in women with PCOS, investigators recently conducted a cross-sectional study including 600 Caucasian women diagnosed with PCOS between May 2008 and May 2013 and 125 women matched for body mass index.

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NAFLD, which was diagnosed by an NAFLD liver fat score, was identified in 50.6% of women with PCOS, compared with 34.0% of controls. Women with PCOS had higher readings for waist circumference, lipid accumulation product (a combination of waist circumference and fasting triglyceride levels), insulin resistance, total cholesterol, and triglycerides than controls. Upon further analysis, insulin resistance and lipid accumulation product were independently associated with NAFLD.

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“This study provided further evidence that PCOS women are more prone to develop NAFLD compared with non-PCOS premenopausal women, and that features of the metabolic dysfunction that characterize PCOS are the main factors implicated in the development of NAFLD in these patients,” says Dr. Vassilatou, who wasn’t involved with the study. “Some research also suggests that androgen excess, which is a key feature of PCOS and is interrelated to insulin resistance, may be an additional contributing factor for the development of NAFLD in PCOS.”

Just scratching the surface

Dr. Vassilatou says that more research is needed to understand the role of androgens, if any, in the pathophysiology of NAFLD in women with PCOS. Also, long-term follow-up studies are necessary to reveal the range of liver-related outcomes in women with PCOS and to determine the natural history of NAFLD in these women—for example, how often it progresses from its early stages to severe liver disease. It will also be important to investigate whether obese patients with PCOS and NAFLD present more frequently with an advanced stage of liver disease, as reported in a few studies.

Although additional studies are needed to clarify the association between PCOS and NAFLD, accumulating data over the past decade indicate that clinicians should at least be aware of this connection. “Thus, these women should be screened for NAFLD, particularly obese patients with features of the metabolic syndrome. Conversely, premenopausal women with NAFLD should be screened for PCOS,” suggests Dr. Vassilatou.

Despite the need for greater screening, more work is necessary to identify the most appropriate methods, which could include ultrasound, liver function tests, and algorithms such as the NAFLD liver fat score. Furthermore, because there’s no medical therapy of proven benefit for treating NAFLD, well-designed interventional studies—with lifestyle modifications and/or the use of medical therapy targeting insulin resistance, impaired glucose tolerance, and dyslipidemia—are needed to determine the optimal management of affected patients.

To get a sense of where we are now, diet, weight loss, and exercise are currently the cornerstone of therapy and are often combined with insulin sensitizers, hypolipidemic drugs, and hepatoprotective agents, like antioxidants.

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Published: March 17, 2017

References

Fatty Liver Disease On The Rise: What Is It And Can It Be Prevented?

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Most adults would assume that if they avoid drinking an excessive amount of alcohol, their livers will remain healthy. This, though, is far from the truth. TheDallas Heart Study suggests that roughly 30 percent of American adults have nonalcoholic fatty liver disease, which some doctors claim may affect even more — up to five percent more.

Though many doctors attribute the condition’s increasing prevalence to swelling rates of obesity and diabetes, the complete story is much more complicated.

Patient

Fatty Liver Disease 101

The liver is the second largest organ in the body — skin is considered the largest organ. The liver weighs in at about 3 lbs. and plays a role in many bodily functions, including digestion, metabolism, immunity, and the storage of nutrients. Nonalcoholic fatty liver disease is an abnormal accumulation of fat in the liver of people who drink no or little alcohol.

As described by the American Liver Foundation, if more than five to 10 percent of the liver’s weight is fat, then this would be considered steatosis or ‘fatty liver.’ Although up to 80 percent of fatty liver patients won’t experience any problems as a result of the condition, the remainder may progress to nonalcoholic steatohepatitis. In such cases, the fatty liver becomes inflamed and cells become damaged. Nonalcoholic steatohepatitis can even lead to cirrhosis, a fatal illness in which the liver forms scar tissue and eventually ceases to function.

In Western countries, nonalcoholic fatty liver disease (NAFLD) appears to be increasing with estimates of its prevalence ranging between 20 and 30 percent. Worse, researchers estimate that nearly one out of every 10 children in the U.S. — more than seven million children — has nonalcoholic fatty liver disease. Pediatric NAFLD affects more boys than girls, by a ratio of two-to-one.

Yet, most children and adults show no symptoms or signs of the condition. This was certainly the case with Nick Giordano, whose story is featured by the American Liver Foundation.

No Symptoms, No Signs

“To be honest, at times I still feel funny telling people I have liver disease,” Giordano wrote of his condition. “I feel fine, I look normal and chances are that if I didn’t tell you I had liver disease, you would never know.”

The American Liver Foundation notes that people who are overweight or obese, those with diabetes, high cholesterol, or high triglycerides, are the ones who tend to develop NAFLD. Other factors may lead to the condition as well, including poor eating habits and rapid weight loss. Yet, some people have no risk factors but still develop NAFLD. For example, Giordano was only a few pounds overweight and exercised regularly. He even ran marathons. He only discovered the disease when his primary care physician noticed his liver enzymes were elevated. From there, Giordano visited a specialist, who advised dietary changes, weight loss, and avoidance of even casual alcohol consumption. By following his doctor’s guidelines, his enzymes returned to normal levels in just a few months.

Although he doesn’t know what caused his initial diagnosis of NAFLD, Giordano’s grandfather had struggled with liver disease and is considered to be one of the conditions that can increase an individual’s risk. Other risk factors, along with those previously mentioned, include:

  • Certain medications
  • Gastric bypass surgery
  • Metabolic syndrome
  • Toxins and chemicals, such as pesticides
  • Wilson’s disease

One other risk factor may be ethnicity, according to recent studies.

Asians and Hispanics At Increased Risk

Researchers from the University of Chicago conducted a retrospective study to examine the relationship between ethnicity and NAFLD. In comparison to whites, African Americans showed a lower degree of fatty liver while Asians and Hispanics showed a greater tendency than whites and other ethnicities combined. In particular, studies on Mexican-Americans suggest that one gene, PNPLA3, may occur often in the Mexican-American population and may be linked to the condition.

It is important to remember that in the majority of cases, nonalcoholic fatty liver disease will not lead to complications and will not present symptoms. When it is discovered, doctors typically treat the condition by treating the risk factors. For example, in the case of Giordano, his doctor worked to help him eliminate the handful of behaviors — overeating, the occasional drink — that might contribute to the condition. In cases of high cholesterol, patients might be advised to manage their low-density lipoprotein (LDL) levels; in cases of obesity, patients are advised to lose weight.

“Throughout the last few years I have heard countless stories from other liver patients,”Giordano noted. “Some have been inspiring and others have been heartbreaking.” Having made the necessary changes to correct an issue that potentially may have developed into serious illness, he counts himself lucky to be alive and therefore able to make a difference.

Sources: Bellentani S, Scaglioni F, Marino M, Bedogni G. Epidemiology of non-alcoholic fatty liver disease. Digestive Diseases. 2010.

Mohanty SR, Troy TN, Huo D, et al. Influence of ethnicity on histological differences in non-alcoholic fatty liver disease. Journal of Hepatology. 2009.

Davis JN, Le KA, Walker RW, et al. Increased hepatic fat in overweight Hispanic youth influenced by interaction between genetic variation in PNPLA3 and high dietary carbohydrate and sugar consumption. American Journal of Clinical Nutrition. 2010.

More children are suffering from fatty liver disease.

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DEAR MAYO CLINIC: I recently read that fatty liver disease is becoming common in young children. What’s the cause of this condition? How is it diagnosed, and can it be reversed?

ANSWER: The number of children who have fatty liver disease is rising. Currently, about 10 percent of children in the U.S. have this disease. It is the most common cause of childhood chronic liver disease in this country. The increase is linked to the childhood obesity epidemic, as fatty liver disease is often caused by excessive weight gain. If it is caught and treated early, the disease typically can be reversed through lifestyle changes, including diet and exercise.

The liver is one of the largest organs in the body. About the size of a football, it is located on the right side of the abdomen, behind the lower ribs. Fatty liver disease (also called nonalcoholic fatty liver disease) occurs when fat builds up in the liver of people who drink little or no alcohol.
Typically the disease causes few, if any, symptoms. Many people with fatty liver disease have it for years and don’t know it. It is important for the disease to be diagnosed, however. If left unchecked, it could eventually lead to liver function problems, especially in children.

The most common cause of fatty liver disease in children is obesity. In children who are at a healthy body weight, fatty liver disease can also be the result of rare metabolic disorders, such as Wilson’s disease or cystic fibrosis, among others.

A doctor may suspect fatty liver disease if a blood test shows that a child’s level of liver enzymes is higher than normal, especially if the child is overweight. The disease also may be discovered through an imaging exam, such as an ultrasound. A diagnosis of fatty liver disease can be confirmed by microscopic examination of a small sample of tissue removed from the liver, a procedure known as a liver biopsy.

If caught while still in the early stages, fatty liver disease may be reversible. In children who are overweight, weight loss often is key to treating the disease. Weight loss usually is best accomplished with a combination of a healthy diet and regular physical activity.

In general, there are some strategies all families can use to help children reach and maintain a healthy weight. For example, make sure you have lots of healthy food choices available in your home. Buy plenty of fruits and vegetables. Cut down on convenience foods, such as cookies, crackers and prepared meals that are high in sugar and fat. Limit sweetened beverages, including fruit juices. These drinks are high in calories and low in nutritional value. They also can make a child feel too full to eat healthier foods.

Encourage your child to be physically active. This not only helps with weight loss, but also builds strong bones and muscles and helps a child sleep better at night. Keep in mind that activity does not have to be structured exercise to burn calories and improve fitness. Playing outdoors, jumping rope and going for hikes can all be good ways for a child to be active.

It is very important that children and teens avoid using supplements to help with weight loss or building muscle. Some of these supplements have recently been associated with acute liver failure and other dangerous health outcomes.

Don’t start a child on a specific weight-loss program before talking with his or her health care provider. It’s important that a weight-loss approach be tailored to a child’s individual situation and needs, including the child’s age and if he or she has any other health problems. — Samar Ibrahim, M.B., Ch.B., Pediatric Gastroenterology, Mayo Clinic, Rochester, Minn.