Multiple Drugs Advance for Fatty Liver Disease


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


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


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%.

2

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.

3

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

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


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.


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.