HEP Spring 2020

A SMART+STRONG PUBLICATION SPRING 2020 HEPMAG.COM

Living With NASH

Fighting fatty liver disease

Terri Milton

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RHA520645.pgs 02.07.2020 13:11

ESA

FROM THE EDITOR

I Will Survive

T

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CONTENTS 1 FROM THE EDITOR Advocating for people with fatty liver disease

he word hepatitis generally describes inflammation of the liver. The Ancient Greek word hepa refers to the liver and -itis means inflammation (as in arthritis).

Inflammation of the liver—hepatitis— has several possible causes. Perhaps the most commonly known are viruses, including hepatitis A, B and C viruses.

However, other microorganisms can also cause hepatitis.

Other causes include toxins and chemicals, such as excessive amounts of alcohol; autoimmune diseases that cause the immune system to attack healthy tissues in the body; and fatty liver disease.

When fat accumulates, the liver can become inflamed and damaged. Excess use of alcohol can cause the liver to become fatty, a condition known as alcoholic liver disease. Non-alcoholic fatty liver disease (NAFLD) occurs when the cause of the fatty liver is not alcohol.

Non-alcoholic steatohepatitis (NASH) is a condition that occurs when fat accumulation has resulted in scarring and other damage to the liver. Cirrhosis may develop, which can lead to liver cancer or liver failure. NASH is no joke.

Terri Milton knows about the hardships of NASH all too well. She has had the condition for 20 years. Despite the challenges, her experience living with NASH has taught her not to let the disease get the best of her and to enjoy life.

“You have to have things to look forward to,” Milton says. “Because sometimes the ‘right now’ sucks!” Regardless of all she has endured with NASH, “I’m smiling,” she says, “because this journey has given me an opportunity to meet some of the most amazing people on

earth.” Go to page 6 to read more.

In addition to sharing a personal story of living with NASH, this special issue of Hep focusing on fatty liver disease goes into a lot more detail about the condition.

Although many people are unfamiliar with fatty liver disease, it is estimated that about 20 million Americans are living with NASH. As a result, it is important to understand the basics of fatty liver disease, including how the condition progresses and how to manage it. Go to page 2 to learn more.

Currently, there are no approved medications for advanced fatty liver disease.

However, a number of treatments for NASH have shown promise in recent mid-stage clinical trials.

Go to page 4 to read the latest about upcoming treatments and how fatty liver affects teens and people living with HIV.

ORIOL R. GUTIERREZ JR. EDITOR-IN-CHIEF

Want more info? Visit hepmag.com • facebook.com/hepmag • twitter.com/hepatitismag

2 BASICS What is fatty liver disease? • healthy liver tips • NAFLD progression • managing fatty liver disease

4 CARE & TREATMENT Will NASH treatments succeed? • weight woes with fatty liver • fatty liver can hit lean teens • treating fatty liver in people with HIV

6 PROFILE Terri Milton is determined not to let advanced fatty liver disease get the best of her.

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BASICS

BY LIZ HIGHLEYMAN

Healthy Liver Tips While research is underway to develop new therapies for fatty liver disease, here are steps you can take to keep your liver healthy.

Fatty liver disease involves the buildup of fat in the liver. This triggers inflammation, which over time can lead to serious complications, including cirrhosis, liver cancer and the need for a liver transplant. There are currently no approved medications for fatty liver disease, and its prevention and management rely on lifestyle changes, such as weight loss and exercise.

Fat accumulation in liver cells, known as steatosis, can have several causes. People who drink heavily may develop alcoholic fatty liver disease.

Certain drugs and environmental toxins can also lead to steatosis.

When it occurs in people who do not drink much, the condition is known as non-alcoholic fatty liver disease (NAFLD) or its more severe form, nonalcoholic steatohepatitis (NASH).

Fatty liver disease is increasingly recognized as part of metabolic syndrome, a cluster of conditions that raise the risk of cardiovascular disease. It is commonly linked to obesity, though some lean people develop NAFLD too. People with fatty liver dis-

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ease often also have insulin resistance, type 2 diabetes, abnormal cholesterol and triglyceride levels, and high blood pressure. Lifestyle factors, including being overweight—especially having excess fat around the waistline—eating an unhealthy diet and lack of physical activity, play a role in the development of NAFLD. People with genotype 3 of hepatitis C virus are more likely to develop fatty liver disease than those with other strains of the virus.

NAFLD and NASH are responsible for a growing proportion of advanced liver disease in the United States and worldwide. Experts estimate that up to a third of Americans have fatty liver disease, and the proportion is rising.

The condition is also becoming more common among children and adolescents. Latinos have a higher rate of fatty liver disease than African Americans or whites. Now that hepatitis B can be prevented with a vaccine and hepatitis C can easily be cured with antivirals, NAFLD and NASH are expected to become the leading reason for liver transplants in the U.S.

minutes per week). regular, good• Get quality sleep. vaccinated • Get against hepatitis A and B. your doctor • Tell about any medications, herbs, supplements and street drugs you use. medical • Follow advice for keeping diabetes and high cholesterol in check. regular follow-up • Get tests to monitor for worsening liver disease.

ALL IMAGES: ISTOCK

What Is Fatty Liver Disease?

or cut down • Avoid on alcohol. a healthy • Maintain weight. a healthy, • Eat balanced diet. regularly • Exercise (ideally at least 150

NAFLD Progression Fat accumulation in the liver usually progresses gradually as fat buildup triggers inflammation that eventually leads to worsening liver damage. As the liver tries to repair itself, it can develop scar tissue, known as fibrosis. There are four stages of fibrosis: mild (Stage F1), moderate (F2), advanced (F3) and cirrhosis (F4). People with cirrhosis are at risk of developing hepatocellular carcinoma— the most common type of primary liver cancer—and end-stage liver failure.

NAFLD often has no symptoms during its early stages.

But as fibrosis worsens, people may experience fatigue, gastrointestinal problems and abdominal pain. People with cirrhosis may have spiderlike blood vessels, jaundice (yellowing of the skin and whites of the eyes), dark urine and pale-colored stools.

Scar tissue can block blood flow through the liver, leading to portal hypertension.

Symptoms of advanced liver disease—known as decompensated cirrhosis— include fluid accumulation in the abdomen (ascites) and bleeding blood vessels in the esophagus or stomach. At the most advanced stage, when the liver is no longer able to filter out ammonia and other toxins, people may develop confusion and other mental symptoms, known as hepatic encephalopathy.

There are currently no simple tests for fatty liver disease. Blood tests may show elevated levels of ALT and other liver enzymes linked to inflammation and liver damage. Ultrasound, MRI or CT scans may be used to reveal fat in the liver. However, these scans do not show whether the condition has progressed to NASH. Transient elastography (FibroScan) and other noninvasive tests can show whether fibrosis has developed. A liver biopsy, which uses a needle to collect a tissue sample to examine under a microscope, is the most accurate way to diagnose liver inflammation, fibrosis and NASH. Biopsies may reveal liver cells “ballooning” as they fill with fat.

Managing Fatty Liver Disease Lifestyle changes are the main approach for managing fatty liver disease. These include eating a healthy diet, increasing physical activity and losing weight. Experts recommend getting at least 150 minutes of moderate exercise each week. Even a small amount of weight loss—as little as 5%— can lead to fatty liver improvement. But weight loss is difficult to achieve and maintain. Some research shows that people with NAFLD may have more trouble losing weight than others.

Extensive research is underway to develop medications to treat NAFLD and NASH. Fat and glucose metabolism and the development of fibrosis are complex, and scientists are taking a variety of approaches to manage fatty liver disease, targeting different steps in the process.

But progress has been slow.

Several experimental drugs that produced favorable changes in biomarkers such as ALT, blood fats and glucose levels in early studies did not significantly improve fibrosis in larger clinical trials. Many experts expect that a combination approach will be needed to successfully manage NAFLD and NASH.

hepmag.com SPRING 2020 HEP 3

CARE & TREATMENT

BY BENJAMIN RYAN

Will NASH Treatments Succeed?

Currently, there are no approved medications for advanced fatty liver disease. But a number of treatments for non-alcoholic steatohepatitis (NASH) have shown promise in recent mid-stage trials.

A Phase IIb trial randomly assigned nearly 400 people with NASH and liver fibrosis to receive a placebo or one of three oral doses of Cirius Therapeutics’ insulin-sensitizing drug MSDC-0602K. After 12 weeks, those who received the two higher doses saw improved glucose metabolism and insulin resistance as well as lower ALT, AST and GGT liver enzyme and alkaline phosphatase levels, which are tied to liver damage and inflammation.

However, MSDC-0602K did not improve liver health according to biopsies.

Two different doses of Novartis’s FXR agonist tropifexor are under investigation in an ongoing Phase II trial of 48 weeks of treatment in 152 people with NASH and moderate to severe fibrosis. Results at the 12-week mark showed that the highest dose was associated with a rapid decline in participants’ ALT and GGT levels and a reduction in liver fat content.

Both tropifexor doses were associated with weight loss, lower LDL (bad) cholesterol and higher HDL (good) cholesterol.

Another Novartis drug, licogliflozin, was studied at two doses in a Phase IIa trial among 77 people who either had NASH and fibrosis or were overweight, had type 2 diabetes and a high ALT level. After 12 weeks, the higher dose led to a decline in ALT, while AST, GGT and HbA1c blood glucose levels and liver fat content declined in both dose groups.

Lastly, a Phase II trial of three doses of Zydus’s saroglitazar included 106 people with different stages of fatty liver disease. After 16 weeks, all doses led to a decline in ALT and liver fat content, while insulin resistance and fasting insulin decreased only in the highest-dose group.

Further research in larger trials will help determine whether these drugs offer long-term clinical benefits rather than just biomarker improvements as well as whether they may be useful as part of combination treatment with other medications.

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Losing weight may be especially difficult for people with non-alcoholic fatty liver disease (NAFLD), but many can succeed via an intensive weight loss program.

“Globally, obesity and NAFLD are an increasing cause of significant morbidity and mortality, with few effective weight loss strategies available,” says Ann Farrell, MBBS, of St. Vincent’s Hospital in Melbourne.

Farrell and her colleagues conducted a retrospective study of obese individuals attending an outpatient weight management clinic between July 2015 and February 2019. Of the 211 people included in the final analysis, 53% had NAFLD. The participants were put on a ketogenic, very low energy diet that consisted mainly of meal-replacement drinks and contained 800 calories daily for 12 weeks or until they lost at least 5% of their body weight.

After three months, 49% of people with NAFLD and 67% of those without the condition achieved this weight loss target.

By six months, these rates had risen to 61% and 75%, respectively.

Having fatty liver disease was the only factor that predicted not crossing the 5% weight loss threshold.

ALL IMAGES: ISTOCK (MODELS USED FOR ILLUSTRATIVE PURPOSES ONLY)

Weight Woes With Fatty Liver

Fatty Liver Can Hit Lean Teens

Nonobese adolescents may be an underrecognized risk group for non-alcoholic fatty liver disease (NAFLD), according to recent research.

Praveen Selvakumar, MD, a pediatric gastroenterologist at the Cleveland Clinic, and colleagues penned an editorial to this effect in the Journal of Pediatric Gastroenterology and Nutrition.

A study led by Selvakumar and published in the same journal analyzed nationally representative

data spanning 2005 to 2014 regarding 1,482 lean 12- to 18-year-olds. On average, 8% of them were suspected of having fatty liver disease.

Factors associated with a higher risk of suspected NAFLD included various indicators of metabolic syndrome, such as low HDL (good) cholesterol, high triglycerides and insulin resistance.

“NAFLD could be considered in lean adolescents with elevated ALT [liver enzymes], especially when associated with metabolic syndrome components and other [causes] of elevated ALT have been ruled out,” Selvakumar and colleagues wrote.

Selvakumar believes that multiple factors likely drive NAFLD in lean adolescents, including excess abdominal fat, which can prompt insulin resistance.

Additionally, some young people may be genetically predisposed to the condition.

To combat fatty liver in adolescents, Selvakumar recommends weight loss: A 10% loss in body weight generally improves the condition. Avoiding excess carbohydrates, simple sugars, candies and juices; reducing portions and calorie intake; and following a Mediterranean diet may also help. In addition, both aerobic activity and resistance exercise can led to a decrease in liver fat.

Treating Fatty Liver in People With HIV The injectable hormone Egrifta (tesamorelin) can improve liver health in people with HIV who have non-alcoholic fatty liver disease (NAFLD).

A recent study enrolled 61 people with HIV and NAFLD, 33% of whom also had the more severe form of the liver disease, nonalcoholic steatohepatitis (NASH). The participants were randomized to receive daily Egrifta or placebo injections.

After one year of treatment, those who received Egrifta had better liver health than those in the placebo group, according to their hepatic fat function (HFF).

HFF, which refers to the ratio of fat to other liver tissues, is considered healthy when it is under 5%. Thirty-five percent of those in the Egrifta group saw

their HFF normalize, compared with just 4% of the placebo group. Between the study’s outset and the one-year mark, Egrifta reduced HFF by 37%.

Those in the Egrifta group also saw greater declines of biomarkers associated with inflammation and liver damage, including ALT liver enzymes.

“Given the increased prevalence and progression rates of fatty liver disease in HIV, the study addresses a critical need in the HIV population and suggests a potentially useful therapeutic that should now be tested further in the HIV population,” said study coauthor Steven Grinspoon, MD, chief of the metabolism unit at Massachusetts General Hospital in Boston.

hepmag.com SPRING 2020 HEP 5

PROFILE

Terri Milton has lived with NASH for 20 years.

I’m Still Standing With a proper diet, exercise and a great care team, Houstonian Terri Milton is determined not to let advanced fatty liver disease get the best of her.

By Tim Murphy Photography by Robert Seale

T

erri Milton loves life. The 56-year-old Houstonian

of Mexican descent, a former realty executive and school bus driver, blisses out on singing with her church group, baking cookies with her grandkids and traveling throughout the United States with her husband, Doug.

“You have to have things to look forward to,” she says.

“Because sometimes the ‘right now’ sucks!”

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She should know. For 20 years, Milton has lived with complications from non-alcoholic steatohepatitis (NASH), an advanced form of fatty liver disease that affects roughly 20 million Americans and, because of a mix of genetics and lifestyle, impacts Latinos at a higher rate.

Milton’s NASH journey began when routine blood tests revealed that her liver enzymes were high. Her primary care provider sent her to a liver specialist, who told her, “You

have fatty liver, but don’t worry about it—everyone does.” So Milton didn’t worry and went on with her life.

But by 2015, she was having regular abdominal pain, which was diagnosed as irritable bowel syndrome. Two years later, while in an emergency room for severe pain, she was told she had a gallstone. Surgery to remove it revealed that her liver was rough and nodular with scar tissue, rather than smooth, as a healthy liver should be. Three biopsies later, she was told she had NASH as well as cirrhosis (severe liver scarring).

That, says Milton, is when all hell broke loose. “Suddenly, I went from not having any symptoms to gaining 30 pounds in a week.” The weight gain was the result of ascites, a buildup of fluid caused by advanced liver disease. She ended up in the hospital again. “I was sopping wet all the time,” she recalls. “I continued to drain two to three liters of fluid daily for almost two weeks. I thought, I didn’t sign up for this.

What in the world is going on?”

Soon after, she ended up in an ER again, this time with hepatic encephalopathy, a condition that develops when a damaged liver can no longer filter out toxins and they make their way to the brain, impairing cognition. “The one thing I was afraid of was losing my ability to think and speak, and now I wasn’t able to,” she recalls.

Medications quelled the ascites. But

as I can to be active. Part of cirrhosis is muscle wasting, so the more you move, the stronger you are.” She got herself a smart watch to track her daily steps. “Some days I get in 500 steps, others 2,000.”

Then there are the meds. She’s on two different diuretics to avoid fluid buildup. She’s taking one med for irritable bowel syndrome, another to treat her high blood pressure, another to treat blood clots, 5,000 IU of vitamin D-3 “because my liver can’t process vitamin D,” two different kinds of insulin for her diabetes and a daily antacid “to keep everything calm.”

As for diet, she has to keep her sodium to below 2,000 milligrams a day as well as watch her sugar and carbohydrates to control her blood sugar, so she leans heavily on eggs with homemade salsa; steel-cut oatmeal with no added sugar; fresh fruit; nuts; salads; lean proteins, like fish, chicken and turkey; and wild rice and quinoa.

She admits that her story conveys a strong message about preventing NASH, diabetes and high blood pressure—all of which are influenced by genetic factors and obesity. “It’s not about going on a crash diet,” she says. “It’s a permanent lifestyle, what you eat and what you do. Sodas, muffins, cake, cookies—all the things that make you smile? Save them for small portions on special occasions.”

As for exercise, says Milton, “You have to start where you are. If you want to run a marathon but you haven’t walked a block, that’s not realistic. Today, get up and walk to the end of your street and back, and build on that. ” She also suggests counting steps with a smartphone app, Apple Watch, Fitbit or similar device.

“The people I’ve met along the way are incredible.”

Milton and her care team decided it was time to consider a liver transplant.

The first evaluation for the procedure required 17 vials of blood. On top of all this, Milton had type 2 diabetes, which was causing gastroparesis, a painful condition that renders the stomach unable to digest food at a normal rate.

“I felt like I was playing Whac-AMole, one problem after another,” says Milton. A further defeat: Her MELD score, used to prioritize people for liver transplants, was too low. “It was crazy that my liver was still functioning so well that it didn’t affect my score.”

Amid all this, she had lost her appetite for life. “I was sleeping 14 hours a night. I’d gone from being a very social, active person to someone who wanted to cry at the thought of leaving the house.”

Then, on top of all that, she found out in May 2018 that she had hepatocellular carcinoma—yes, liver cancer. Two months later, she had radiofrequency ablation to destroy the tumor. In August, a scan showed that the cancer was gone, but in November, another showed that it had come back.

Early in 2019, she had a TACE—transarterial chemoembolization—a procedure that delivered chemotherapy beads to the tumor via a catheter threaded through a vein in her groin. Despite side effects such as pain, severe nausea and some hair loss, Milton said the treatment was “not that bad overall—it’s a miracle treatment.”

So this is where Milton is today, living daily with complications of NASH. That means, in her words, “trying as hard

For those already dealing with NASH,

Milton says, “You need a team of doctors you can trust, and you need to be your own advocate and learn the language.” She recommends starting at the website of the Global Liver Institute (GLI), an organization she has become involved with, as well as the Facebook group she co-moderates, Cirrhosis and Liver Disease Support Group: Helping Each Other!

Milton is determined to make the best of her holding pattern. She wants to go back to school to become a social worker to help people living with chronic disease, and she and Doug are determined to travel to the roughly 10 states they’ve not yet visited, including Alaska and Hawaii.

Yet despite all she has endured with NASH, “I’m smiling,” she says, “because this journey has given me an opportunity to meet some of the most amazing people on earth—lawyers, caregivers, patients and people like [GLI founder] Donna Cryer. I’ve traveled to New York City to speak to researchers, and I’m part of the process of looking for a cure.”

That’s what keeps her spirits up. “I have days where I cry because it’s so overwhelming,” she says. “But the people I’ve met along the way are incredible, and that’s what I love.” ■

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